Abstract
Since the discovery of glucocorticoids in the 1940s and the recognition of their anti-inflammatory effects, they have been amongst the most widely used and effective treatments to control inflammatory and autoimmune diseases. However, their clinical efficacy is compromised by the metabolic effects of long-term treatment, which include osteoporosis, hypertension, dyslipidaemia and insulin resistance/type 2 diabetes mellitus. In recent years, a great deal of effort has been invested in identifying compounds that separate the beneficial anti-inflammatory effects from the adverse metabolic effects of glucocorticoids, with limited effect. It is clear that for these efforts to be effective, a greater understanding is required of the mechanisms by which glucocorticoids exert their anti-inflammatory and immunosuppressive actions. Recent research is shedding new light on some of these mechanisms and has produced some surprising new findings. Some of these recent developments are reviewed here.
Keywords: Glucocorticoid, Inflammation, 11β-Hydroxysteroid dehydrogenase
1. Introduction
Natural and synthetic glucocorticoids remain at the forefront of anti-inflammatory and immunosuppressive therapies. They are widely used to treat both acute and chronic inflammations, including rheumatoid arthritis, inflammatory bowel disease, multiple sclerosis, psoriasis and eczema, as well as being used in treatment of certain leukaemias and in immunosuppressive regimes following organ transplant. At any one time, an estimated ∼1% of the total adult population of the UK receives oral glucocorticoid therapy (van Staa et al., 2000). However, long-term use of oral glucocorticoids is associated with serious side effects, including osteoporosis, metabolic disease and increased risk of cardiovascular disease (Wei et al., 2004; Souverein et al., 2004; de Vries et al., 2007; Vegiopoulos and Herzig, 2007)—in themselves, somewhat paradoxically, inflammatory conditions. Over the 60 years since the discovery of glucocorticoids, much has been learnt of the molecular mechanisms by which they act (recently reviewed; Perretti and Ahluwalia (2000), Necela and Cidlowski (2004), Yeager et al. (2004), Rhen and Cidlowski (2005), Smoak and Cidlowski (2004), Tuckermann et al. (2005), Kleiman and Tuckermann (2007), Newton and Holden (2007) and De Bosscher and Haegeman (2009)), with milestones being the characterisation of the glucocorticoid receptor (GR) as a DNA binding protein that regulates transcription initiation (reviewed, Yamamoto (1985)), the cloning of GR (Hollenberg et al., 1985; Miesfeld et al., 1986) and the discovery that many of the immunosuppressive actions of glucocorticoids are mediated by interference with signalling by the key inflammatory transcriptional regulators; NF-κB and AP-1 (Jonat et al., 1990; Yangyen et al., 1990; Heck et al., 1994) (reviewed, McKay and Cidlowski (1999)). However, much also remains unknown and the past few years have provided crucial mechanistic insights into the dynamic nature of GR interactions with DNA and higher order chromatin structures, into the subtleties of ligand effects on GR function, the regulation of endogenous ligand access to GR, glucocorticoid effects on leukocyte differentiation and function and the mechanistic basis for some of the repressive actions of glucocorticoids, critical for their anti-inflammatory effects.
2. Inflammation and its resolution
The host inflammatory response is a primary defence mechanism engaged immediately following injury or infection which is necessary to restore homeostasis following successful elimination of the injurious agent, ultimately leading to resolution and tissue repair. Although categorically distinct, the innate (the relatively non-specific immediate host defence system that provides a rapid reaction to infection and tissue damage) and adaptive (the more slowly acquired, highly antigen-specific response) immune systems interact and often overlap during an inflammatory response. Indeed, although acute inflammation is largely mediated by the innate immune system, the adaptive immune system often plays a major role in chronic inflammatory disease, with dysregulated lymphocyte responses.
Inflammation is initiated at the site of injury by resident cells, particularly mast cells and resident macrophages, which release pro-inflammatory mediators including bioactive amines, lipid mediators and cytokines—typically TNF-α and IL-1. These cause vasodilation, increased capillary permeability (humoral response) and leukocyte emigration into injured tissues (cellular response), resulting in the hallmark pain, heat, redness and swelling of inflammation as well as generating a chemotactic gradient to guide and activate recruited cells to the site of injury. Although specific characteristics depend on the immune exposure (e.g. irritant vs pathogen), the recruitment process and activation of inflammatory cells are common. Activated granulocytes, crucial to contain microbial infection, are rapidly attracted to the inflamed site, followed by monocyte emigration from blood vessels and subsequent maturation into macrophages. Once at the inflamed site, neutrophils undergo constitutive apoptosis, functionally isolating them from the inflammatory environment by loss of stimulated chemotaxis, phagocytosis, degranulation and respiratory burst (Haslett et al., 1991; Whyte et al., 1993), whilst at the same time, facilitating safe removal of their potentially histotoxic contents by macrophages (Savill et al., 2002). Foreign antigens are taken up by antigen presenting cells; particularly dendritic cells, but also macrophages, that then migrate to draining lymph nodes where they instruct the adaptive immune system (T and B lymphocytes), shaping the subsequent immune response. As the inflammatory response progresses and evolves, mononuclear cells predominate and resolution normally ensues. Successful resolution of acute inflammation is an active and highly regulated process and dependent on mechanisms engaged early in the inflammatory response that programme the trajectory and form of the subsequent resolution (reviewed Savill et al. (2002), Gilroy (2004) and Serhan and Savill (2005)). Persistence of the initiating stimulus invariably leads to chronic inflammation, with the typical dysregulation between destructive inflammatory and excessive healing responses seen in diseases such as arthritis, atherosclerosis and asthma.
3. Glucocorticoids and inflammation
Glucocorticoids inhibit many of the initial events in an inflammatory response. They also promote the resolution of inflammation although the mechanisms by which they do so have received less attention than those associated with suppression of the initial response. Acutely, glucocorticoids inhibit the vasodilation and increased vascular permeability that occurs following inflammatory insult and they decrease leukocyte emigration into inflamed sites, effects that require new protein synthesis (reviewed Perretti and Ahluwalia (2000)). They also alter leukocyte distribution/trafficking (McEwen et al., 1997), death/survival (McEwen et al., 1997; Ashwell et al., 2000; Planey and Litwack, 2000; Herold et al., 2006; McColl et al., 2007) and, importantly, alter cellular differentiation programmes, thus shaping the subsequent response (see below).
Most of the anti-inflammatory and immunosuppressive actions of glucocorticoids are attributable either directly or indirectly to the transcriptional effects of GR agonism which alters transcription of numerous genes in leukocytes, both up and down (Ashwell et al., 2000; McEwen et al., 1997). Although expression of mineralocorticoid receptor (MR), which binds glucocorticoids with high affinity in the absence of 11β-hydroxysteroid dehydrogenase type 2 (11β-HSD2; see below), has been reported in immune cells (Miller et al., 1990; Barish et al., 2005; Lim et al., 2007) (which do not normally express 11β-HSD2 Gilmour et al. (2006), Lim et al. (2007)), it appears of little consequence to the anti-inflammatory effects of glucocorticoids, and may even have pro-inflammatory effects (Lim et al., 2007; Harizi et al., 2008). It should also be noted that some anti-inflammatory effects of glucocorticoids are apparent within minutes and a number are independent of the transcriptional effects of GR (see for example Croxtall et al. (2002), Limbourg et al. (2002) and Stellato (2004)). Notably, glucocorticoids repress transcription of many genes encoding pro-inflammatory cytokines and chemokines, cell adhesion molecules and key enzymes involved in the initiation and/or maintenance of the host inflammatory response (reviewed Barnes (1998), Perretti and Ahluwalia (2000) and Smoak and Cidlowski (2004)). Many of these genes are commonly over-expressed during chronic non-resolving inflammation. Intriguingly, recent data have shown that whereas glucocorticoid administration 1 h following endotoxin (lipopolysaccharide, LPS) challenge is immunosuppressive, administration of the same glucocorticoid dose prior to LPS challenge augments immune responses (Frank et al., 2010). This was true in both the brain and the liver, raising the possibility that chronic hypothalamic–pituitary–adrenal (HPA) axis activation (as may occur during chronic inflammation for example) exaccerbates inflammation in the brain and elsewhere (reviewed in Sorrells et al. (2009)).
Until recently, it was widely believed that the repressive, anti-inflammatory effects of glucocorticoids were dependent on the ability of GR to inhibit the activity of crucial transcriptional regulators of pro-inflammatory genes, including NF-κB and AP-1, by a mechanism termed “transrepression”. This contrasted with the metabolic actions of glucocorticoids which require gene activation by GR. This view has recently been revised, with the discovery that key anti-inflammatory actions of glucocorticoids are brought about through gene activation (Clark, 2007) (and see below).
4. The repressive actions of glucocorticoids
The ability of GR to repress the activity of NF-κB and AP-1 as well as other key immunomodulatory transcription factors has been a major focus of research into the mechanisms underlying the anti-inflammatory effects of glucocorticoids. Although a role for transactivation by GR in repression of NF-κB was implicated – inducing expression of the NF-κB inhibitor, IκBα (Auphan et al., 1995; Scheinman et al., 1995) – this was restricted to certain cell types and did not appear to be a universal mechanism (Heck et al., 1997; Wissink et al., 1998). Biochemical and genetic evidence suggested that negative regulation by a transrepression (or “tethering”) mechanism independent of DNA binding by GR underpinned the repressive effects of glucocorticoids (reviewed Smoak and Cidlowski (2004) and Clark (2007)) and this, by extension, was thought to be responsible for their clinical efficacy. In contrast to gene activation by GR, which at the time was believed to occur exclusively through homodimers of GR binding to palindromic glucocorticoid response elements (GREs) (Beato et al., 1996; Karin, 1998), transrepression involves direct protein-protein binding of GR to other transcription factors and interference with their mechanism of action. The interaction requires the DNA binding domain of GR (but not DNA binding per se) and does not require conventional homodimerisation of GR (Barnes, 1998; Karin, 1998; Smoak and Cidlowski, 2004). Transrepression was not affected by mutation of alanine 458 to threonine (A458T) within the dimerisation interface of the DNA binding domain that dramatically reduces GR transactivation of the MMTV-LTR promoter and the tyrosine aminotransferase (TAT) gene promoter, both classically activated by GR through well-characterised palindromic GREs (Payvar et al., 1983; Grange et al., 1989). Considerable support for the transrepression hypothesis came from in vivo experiments in mice in which the wild-type GR was replaced by the dimerisation (dim) mutant (GRdim mice) (Reichardt et al., 1998). Glucocorticoid-mediated repression of AP-1-dependent transcription and other pro-inflammatory genes was intact in these mice, in contrast to defective GRE-dependent transactivation (Reichardt et al., 1998, 2001). However, transactivation of some genes, including that encoding phenylethanolamine N-methyltrasferase (PNMT), remained intact (Reichardt et al., 1998). It has since emerged that the GRE in the PNMT gene belongs to a different class of GRE to the palindromic consensus, and comprises a series of repeated half sites to which GR directly binds to activate transcription from the PNMT promoter (Adams et al., 2003). Dual specificity phosphatase (DUSP) 1, also known as MKP-1 (mitogen activated protein kinase [MAPK] phosphatase 1), a crucial anti-inflammatory gene (Hammer et al., 2006; Salojin et al., 2006; Zhao et al., 2006; Maier et al., 2007), also remains fully inducible in GRdim mice (Abraham et al., 2006), offering an alternative interpretation of their phenotype. Glucocorticoid induction of DUSP1 may have some similarity to that of PNMT, as recent work has shown the glucocorticoid responsive region in the DUSP1 gene contains 3 closely spaced half sites (Tchen et al., 2009), although a tethering mechanism of activation dependent on C/EBPβ has also been implicated (Johansson Haque et al., 2008). Thus, at least some, but not all, of the dimerisation-independent repressive actions of glucocorticoids may be wholly or partly dependent on induction of DUSP1. Consistent with this, glucocorticoids failed to suppress zymosan-induced inflammation in DUSP1−/− mice, whereas inflammation was suppressed in control mice (Abraham et al., 2006). However, DUSP1−/− mice remain sensitive to the suppressive effects of glucocorticoids in mast cell-dependent anaphylaxis (Maier et al., 2007), implicating other mechanisms in the anti-inflammatory action of glucocorticoids in this model of inflammation. Intriguingly, DUSP1−/− mice are resistant to diet-induced obesity (Wu et al., 2006), raising the possibility that DUSP1 may also be involved in some of the metabolic effects of glucocorticoids.
The anti-inflammatory actions of glucocorticoid-induced genes have been recently reviewed (Clark, 2007). Briefly, as well as DUSP1 and IκB, this class of genes includes IL-10, a potent immunomodulatory and anti-inflammatory cytokine (Couper et al., 2008), Glucocorticoid-induced leucine zipper (GILZ), a protein whose mechanism of action is unclear but which interacts with, and inhibits the function of, NFκB and AP-1 (Ayroldi and Riccardi, 2009) and annexin AI (AnxA1), a calcium-dependent phospholipid binding protein (Perretti and D’Acquisto, 2009). GILZ knockout mice have not been reported, but AnxA1-deficient mice show defective glucocorticoid suppression of inflammation in carrageenin-induced oedema, zymosan-induced peritonitis and antigen-induced arthritis (Hannon et al., 2003; Yang et al., 2004). IL-10-deficient mice develop autoimmune disease and chronic inflammation (Kuhn et al., 1993; Rennick et al., 1995), but effects of glucocorticoids in these mice have not been reported. However, IL-10 has been implicated in negative regulation of corticosterone synthesis, acting at the adrenal gland (Koldzic-Zivanovic et al., 2006), providing a plausible homeostatic mechanism to terminate HPA axis activation once inflammation is resolving. Like IL-10, administration of AnxA1 can mimic a subset of the effects of glucocorticoids (although in T cells, AnxA1 effects may be opposite to those of glucocorticoids) (Perretti and D’Acquisto, 2009). Similarly, ectopic expression of GILZ in T cells (Delfino et al., 2006; Cannarile et al., 2006, 2009) and dendritic cells (Cohen et al., 2006) can mimic some of the effects of glucocorticoid. Indeed, some of the effects of both IL-10 and AnxA1 may even be mediated by GILZ (Cannarile et al., 2009; Yang et al., 2009a), although as IL-10, AnxaA1 and GILZ all alter differentiation or activation state of immune cells (Yona et al., 2004; Cohen et al., 2006; D’Acquisto et al., 2007a,b; Couper et al., 2008; Huggins et al., 2009), such conclusions remain tentative.
Glucocorticoids induce GILZ in a variety of cell types, both immune and non-immune (Clark, 2007), through palindromic GREs in the 5′-flanking region of the GILZ gene (Wang et al., 2004; van der Laan et al., 2008), dependent on dimerisation of GR (Rogatsky et al., 2003). How they regulate IL-10 and AnxA1 remains unclear. In vitro, glucocorticoids increase IL-10 expression in monocytes (Mozo et al., 2004), macrophages (Ehrchen et al., 2007) and, dependent on antigen presenting cells, in T cells (Richards et al., 2000), but whether this is related to glucocorticoid-driven alterations in cellular differentiation (see below) or whether glucocorticoid-induced IL-10 indeed mediates some of the effects of glucocorticoids on differentiation as suggested (Richards et al., 2000) remains unknown. Glucocorticoids increase AnxA1 expression on human monocytes and neutrophils in vivo (Goulding et al., 1990) and in pituitary folliculostellate cells in vitro (Solito et al., 2003) and whilst the underlying mechanisms remain unclear, they appear to involve both non-genomic and genomic actions of glucocorticoids, the latter both modest and relatively slow (Solito et al., 2003). Moreover, glucocorticoids decrease AnxA1 mRNA in T cells (D’Acquisto et al., 2008), raising the possibility that glucocorticoid regulation in adaptive and innate immune cells may be related to differentiation/activation state rather than being a direct regulation.
5. Context-specific gene regulation by GR
Transcriptional repression by GR has always been the subject of debate, as alluded to above, including the extent to which it is dependent or independent of direct GR DNA binding. However, it is agreed that gene activation requires DNA binding by GR. Much of the early work on GR transcriptional activation was based around a consensus GR binding site, comprising two 6 bp “half sites” arranged in an inverted repeat (palindrome) separated by a 3 bp spacer, derived from comparisons of around 20 GR binding sites in promoters including the MMTV-LTR (Beato et al., 1989; Umesono and Evans, 1989). Subsequent work has confirmed this (Reddy et al., 2009) but additionally shown GR-mediated gene regulation to be much more complex (reviewed in detail in Lefstin and Yamamoto (1998), Grange et al. (2001), Hager et al. (2004), Clark (2007) and Biddie and Hager (2009)). A recent unbiased screen of GR binding sites coupled with transcriptome analysis showed that genes activated by glucocorticoid had GR bound within a median distance of 11 kb from the transcription start site whereas repressed genes had GR bound a median of 146 kb from the transcription start site, suggesting that repression occurs independently of promoter-proximal GR binding (Reddy et al., 2009). In silico prediction, genome scanning, chemically directed sequence-specific disruption of GR binding and chromatin immunoprecipitation experiments have shown that sequences that match the GR consensus do not necessarily bind GR in cells (Horie-Inoue et al., 2006; So et al., 2008) and that disruption of GR binding to the conserved half site sequence 5′-WGWWCW-3′ (where W = A/T) only affects a minority of glucocorticoid-regulated genes, both repressed and activated (Muzikar et al., 2009). It has long been clear that many GR binding sites (core sites) are embedded in “composite” glucocorticoid responsive units (e.g. Imai et al. (1990), Alam et al. (1993) and Beato et al. (1996)). Core GR binding sites vary considerably around the consensus (Wang et al., 2004; So et al., 2007) although the precise sequence in and immediately around the core GR binding site in a gene (the glucocorticoid responsive unit) is highly conserved between species (So et al., 2007). Moreover, actual occupancy by GR is influenced by post-translational modification (Blind and Garabedian, 2008) and depends on cell-specific factors (So et al., 2007). Thus, efficient glucocorticoid regulation depends on concomitant binding by other transcription factors at composite elements, to the extent that GR may “tether” at some promoters, retained principally by protein–protein interactions rather than direct interactions with DNA (Lefstin and Yamamoto, 1998). Given that GR homodimerisation, at least of the isolated DNA binding domain, only occurs on DNA binding (Härd et al., 1990; Luisi et al., 1991), then monomers of GR may bind to divergent sequences at composite response elements or by tethering to other transcription factors (Lefstin and Yamamoto, 1998). Thus, the context of the GR binding site is crucial with the outcome – repression, activation or even specificity (MR vs GR) – dependent on the cell-specific complement of transcription factors (Grange et al., 1991; Yoshinaga and Yamamoto, 1991; Pearce and Yamamoto, 1993). Whether and how GR contacts DNA might be critical. The GR DNA binding sequence itself acts as an allosteric regulator of GR function, dictating the pattern of regulation that ensues following GR binding (Lefstin and Yamamoto, 1998; van Tilborg et al., 2000; Meijsing et al., 2009). DNA binding induces conformational changes in the dimerisation interface that expose otherwise silent transcriptional activation surfaces (van Tilborg et al., 2000). These conformational changes are exquisitely sensitive to the DNA sequence, with single base pair differences differentially affecting GR conformation and transcriptional regulation (Meijsing et al., 2009). Further complexity is revealed at the level of chromatin, where GR binding is highly dynamic and invariably occurs at either consititutive or hormone inducible nuclease accessible sites (regions of “open” chromatin) at which the requirement for chromatin remodelling complexes differs (John et al., 2008; Biddie and Hager, 2009). These dynamic and gene-specific differences in chromatin remodelling by GR are likely to be highly cell-specific and could underlie the complex kinetics of glucocorticoid responses, where glucocorticoid responsive genes may exhibit alternate activation and repression, with poor correlation in some cases between GR binding to response elements and target gene response (John et al., 2009). Elucidating the nature of GR interactions with target genes, especially in the immune system, will be crucial to understanding their anti-inflammatory effects, but the challenge will be to establish these actions in physiologically relevant settings.
6. Glucocorticoid effects on immune cell function
GR is widely, almost ubiquitously, expressed. Thus, glucocorticoids affect virtually all immune cells and, moreover, precise effects depend upon differentiation and activation state of the cell (McEwen et al., 1997), making interpretation of in vivo effects in specific cell populations difficult. Nevertheless, several lines of mice with global alteration of GR have provided vital new information about the functions of GR both in regulating the HPA axis and immunity and inflammation. Mice with hypomorphic (GRhypo) or null alleles of GR die neonatally (Cole et al., 1995; Finotto et al., 1999), but haematopoietic progenitors from these mice have been used to reconstitute the immune system in lethally irradiated wild-type mice (Wust et al., 2008). Other models survive and include mice with increased GR density (yGR mice with 2 extra GR alleles) (Reichardt et al., 2000), with decreased GR density (GR+/− mice and anti-sense rat GR transgenic mice, Pepin et al. (1992)) and mice with altered GR function; GRdim (Reichardt et al., 1998) and GRM601L mice (Zhang et al., 2009) (a knock-in of a human GR mutant with increased glucocorticoid sensitivity). In all these models the HPA axis is affected because of the central feedback actions of glucocorticoids, compensating for altered GR function in all but the hypomorphic and null mice. All show inflammatory/immune phenotypes (see below). Recent experiments using conditional GR knockout mice as well as transgenic mice have also shed light on the cell-specific functions of GR during immune and inflammatory responses. Tissue-specific models reported include T cell-specific or myeloid cell knockout of GR as well as transgenic mice with thymus over- and under-expression of GR. Some of the immune and inflammatory phenotypes of these various mice have been reviewed in detail elsewhere (Herold et al., 2006; Kleiman and Tuckermann, 2007) and are discussed below.
6.1. GR functions in T cells
Glucocorticoid action in T cells and, in particular, in thymus, where naive T cells (that have yet to encounter antigen) develop, has been the subject of intensive research yet remains highly controversial. During T cell development, immature thymocytes progress from double negative (for the CD4 and CD8 T cell markers) to double positive cells (CD4+CD8+) which undergo positive selection (only thymocytes that bind MHC complexed with self-antigen survive) and negative selection (against cells that interact too strongly with self-antigen) to mature into either CD4+ or CD8+ single positive cells; the T cell repertoire. Double positive cells, the majority of the thymocyte population, are highly sensitive to glucocorticoid-induced apoptosis (Purton et al., 2004), effective at physiological levels of glucocorticoids (Jaffe, 1924). Much in vitro evidence points to a crucial role for glucocorticoids in regulating T cell number, repertoire and function, yet the in vivo evidence is discordant. This topic has been extensively reviewed (Ashwell et al., 2000; Godfrey et al., 2001; Jondal et al., 2004; Bommhardt et al., 2004; Herold et al., 2006) and will only be briefly discussed here. Suffice it to say, complete lack of GR globally, in T cells alone or inability to dimerise (GRdim mice) does not appear to affect thymocyte number or subsets, although these thymocytes are completely glucocorticoid resistant (Reichardt et al., 1998; Purton et al., 2000; Cole et al., 2001; Purton et al., 2002; Brewer et al., 2002) (reviewed in Herold et al. (2006)). Conversely, mice with a global increase in GR levels (yGR mice) or function (GRM604L mice) have normal thymocyte numbers and subsets, yet both lines of mice show increased glucocorticoid sensitivity of thymocytes in vitro (Reichardt et al., 2000; Zhang et al., 2009). However, transgenic mice with increased GR in T cells (directed by the proximal Lck promoter or a doxycycline-inducible CD2 promoter) show reduced thymic cellularity with increased thymocyte sensitivity to glucocorticoids in vitro (Pazirandeh et al., 2002, 2005). Finally, in 2 of 3 models in which GR density is reduced by expression of antisense GR either globally (neurofilament promoter) or in T cells (Lck promoter), thymic cellularity is increased, albeit modestly (Pepin et al., 1992; Pazirandeh et al., 2002). However, the 3rd antisense model (also using the proximal Lck promoter) showed the opposite effect, with reduced cellularity (King et al., 1995) and altered T cell repertoire (Lu et al., 2000). Reconciling these discrepant results will no doubt inform on the cell-specific roles of GR in thymus and T cell selection.
T cell GR is required to survive lethal activation of T cells. Mice with conditional deletion of GR in T cells (in which the Lck promoter was used to drive Cre recombinase-mediated excision of a “floxed” GR gene) showed increased mortality following activation of T cells either by antibody to CD3ɛ or following injection of bacterial superantigen (staphylococcal enterotoxin A), due to failure to repress cyclooxygenase (COX)-2 expression (Brewer et al., 2003). Interestingly, these mice showed much worse tissue damage in the gastrointestinal tract than control mice following T cell activation, although damage in other tissues was similar (Brewer et al., 2003), suggesting a particular role for GR in T cells within the gastrointestinal mucosa in controlling immune activation.
GR is also required in peripheral T cells for the immunosuppressive effects of glucocorticoid therapy in experimental autoimmune encephalomyelitis (EAE; a mouse model of multiple sclerosis) (Wust et al., 2008). Like chimeric mice with GR−/− haemotopoietic cells (following lethal irradiation of wild-type mice and reconstitution with GR−/− haemotopoietic cell progenitors), GRLckCre mice (a second line, distinct from the mice mentioned above) showed an earlier onset of disease than controls (indicating a critical role for endogenous glucocorticoid) which was refractory to dexamethasone treatment (Wust et al., 2008). In control mice, but not in GRLckCre mice, glucocorticoid therapy induced apoptosis of T cells in peripheral lymphoid organs and down-regulated adhesion molecules, thus reducing migration of T cells to the site of inflammation (Wust et al., 2008). Importantly, mice heterozygous for a null mutation of GR (GR+/− mice), with half the normal level of GR (Wang et al., 2006), showed a more severe EAE disease course with greater inflammation in the spinal cord than control mice and were resistant to the suppressive effects of a sub-maximal dose of dexamethasone (4 mg/kg) that was effective in normal mice (Wust et al., 2008). This suggests that GR density in peripheral T cells is a critical determinant of sensitivity and that despite the presence of functional GR, clinical glucocorticoid resistance can arise. However, in sepsis, another model of inflammation, GR in T cells is not required for glucocorticoid suppression (cited as unpublished data in Kleiman and Tuckermann (2007)).
6.2. GR functions in myeloid cells
The phenotype of mice with a conditional deletion of GR in myeloid cells has been reported by 2 groups (Bhattacharyya et al., 2007; Tuckermann et al., 2007; Wust et al., 2008). In both cases, the LysM promoter was used to drive Cre recombinase-mediated excision of a floxed GR gene. This results in efficient excision in macrophages and granulocytes in GRLsyMCre mice, with variable excision in other myeloid cell types including dendritic cells and mast cells (Clausen et al., 1999; Lacy-Hulbert et al., 2007; Tuckermann et al., 2007). Similar to adrenalectomised mice (Bertini et al., 1988), GRLsyMCre mice showed greater mortality following LPS challenge than control mice (Bhattacharyya et al., 2007). This was attributed to failure to induce DUSP1, required to inhibit p38 MAPK activated by engagement of toll-like receptor (TLR) 4 by LPS (Zhao et al., 2006). However, given that GRdim mice show normal glucocorticoid induction of DUSP1 in macrophages (Abraham et al., 2006), yet are susceptible to lethal sepsis (cited in Kleiman and Tuckermann (2007)) as unpublished data), it is likely that other important myeloid cell anti-inflammatory actions of glucocorticoids are also required in this model of inflammation. In contrast to endotoxaemia, mice with deletion of GR in myeloid cells remained fully sensitive to therapeutic suppression of EAE by glucocorticoid, although they did show exacerbated disease (Wust et al., 2008).
GR in myeloid cells, but not T cells, are required for glucocorticoid suppression of contact allergy (a T cell-dependent delayed-type hypersensitivity response, such as occurs in response to metals or poison ivy) (Tuckermann et al., 2007). Whereas T cell deletion of GR (GRLckCre) had no effect, deletion of GR in myeloid cells (GRLysMCre) abolished glucocorticoid suppression of inflammation, allowed persistent leukocyte infiltration into the inflamed area and impaired glucocorticoid suppression of macrophage IL-1β, MCP-1 and MIP-2 secretion (Tuckermann et al., 2007). Interestingly, in contrast to irritant-induced skin inflammation (Reichardt et al., 2001), glucocorticoid repression of T cell-dependent contact allergy did not occur in GRdim mice (Tuckermann et al., 2007), and although TNFα remained glucocorticoid-suppressible in GRdim macrophages, MCP-1 and MIP-2 were not repressed (Tuckermann et al., 2007). Thus, the immunosuppressive effects of GR are likely to result from multiple mechanisms, which are cell-type and stimulus-type dependent.
The elucidation of the cell-specific roles of GR within other leukocyte populations and also within T cell subsets will be informed by future conditional knockouts. Knockout of GR in mast cells, a major target in glucocorticoid suppression of allergic responses (Kassel and Cato, 2002), will be revealing, as will GR disruption in B cells. Like T cells, glucocorticoids also reduce circulating B cell numbers. Consistent with this, blood lymphocyte levels (T and B cells) as well as monocyte/neutrophils (CD11b+ cells) were markedly reduced following reconstitution of irradiated wild-type mice with GRM604L glucocorticoid-hypersensitive haematopoietic progenitor cells (Zhang et al., 2009). Elucidation of the underlying mechanisms may be helpful in the treatment of some early T and B cell leukaemias that respond to glucocorticoids.
7. Glucocorticoids alter leukocyte differentiation programmes
As well as profoundly affecting the function of immune cells, glucocorticoids also alter differentiation programmes of progenitor cells (McEwen et al., 1997). Thus, chronically stressful conditions (when endogenous glucocorticoid production is high) or glucocorticoid pharmacotherapy may alter immune cell differentiation and indeed, probably shape the immune response as it develops (Munck et al., 1984; Rook et al., 1994). This may be of relevance in the induction of peripheral tolerance to allergenic stimuli, a major clinical application of glucocorticoids.
Dendritic cells are key antigen presenting cells that bridge the innate and adaptive immune systems. Immature dendritic cells are activated when they capture, process, then present antigens, maturing into immunostimulatory cells in the process. Activated dendritic cells migrate to draining lymph nodes where they interact with naive T cells to instruct the adaptive immune response. Suppression of dendritic cells maturation and function has been implicated in the immunosuppressive effects of glucocorticoids. However, glucocorticoids do not merely suppress dendritic cell activity, but reprogramme them to so-called “tolerogenic dendritic cells” which can elicit a state of hypo-responsiveness in T cells and induce formation of regulatory T (Treg) cells (Rea et al., 2000; Rutella and Lemoli, 2004; Chamorro et al., 2009; Luther et al., 2009). Differentiation of tolerogenic dendritic cells is dependent, at least in part, on GILZ (Cohen et al., 2006; Hamdi et al., 2007). Exactly how GILZ mediates anti-inflammatory effects currently remains unclear, although it is likely to depend on protein-protein interactions between GILZ and a variety of intracellular signalling proteins, including the inflammatory regulators NF-κB and activated Ras, the latter being a key protein in signalling to MAP kinases (Ayroldi and Riccardi, 2009). Nevertheless, the active suppression of antigen-specific immunity through Treg induction by glucocorticoid-programmed dendritic cells undoubtedly contributes to their efficacy in allergic disease and probably other chronic inflammatory diseases. Interestingly, as well as promoting a tolerogenic phenotype in dendritic cells, glucocorticoids may also contribute to tolerance through direct effects on T cells. Stimulation of CD4+ cells in the presence of glucocorticoid (or even more effectively, together with vitamin D3) induced IL-10-secreting Treg cells, able to regulate Th1 responses and autoimmunity (Richards et al., 2000; Hawrylowicz, 2005). A more complete understanding of these effects will improve clinical use of glucocorticoids.
These dramatic effects of glucocorticoids on haematopoietic cell differentiation are not restricted to dendritic cells. Glucocorticoids induce a similar anti-inflammatory phenotype in macrophage differentiation. Work over the past decade has shown that a key mechanism to resolve inflammation is the recognition and phagocytosis of dying cells by monocytes/macrophages (Savill et al., 2002). Glucocorticoids increase macrophage phagocytosis of apoptotic cells, a strongly anti-inflammatory process (Fadok et al., 1998), by at least 2 mechanisms. In already differentiated human monocyte-derived macrophages, they induce a protein S/Mer tyrosine kinase-dependent apoptotic cell clearance pathway (McColl et al., 2009). However, when included during the differentiation process, glucocorticoids also programme blood monocyte differentiation into a highly phagocytic “anti-inflammatory” macrophage phenotype (Giles et al., 2001; Heasman et al., 2003; Ehrchen et al., 2007), a phenomenon that can be modulated by local cytokine environment (Heasman et al., 2003), may be mediated in part by Anxa1 (Maderna et al., 2005) and which also includes induction of Mer tyrosine kinase as well as other anti-inflammatory genes important in phagocytosis, chemotaxis and protection against oxidative stress (Ehrchen et al., 2007). Whether GILZ plays a similar important role in the glucocorticoid-directed macrophage differentiation programme to that it plays in re-programming dendritic cells has not been addressed. Interestingly, these glucocorticoid-programmed macrophages show down-regulation of adhesion-related proteins (Giles et al., 2001; Ehrchen et al., 2007) suggesting they have increased migratory properties. Importantly, in mouse monocytes, glucocorticoids induced a phenotype with low adhesiveness, high migratory capacity and markers suggestive of a tumour-associated macrophage phenotype (Varga et al., 2008), believed to be important for tumour-associated immunosuppression (Sica and Bronte, 2007). The authors further speculate that this may be a mechanism underlying the higher incidence and faster progression of tumours in patients on long-term glucocorticoid therapy (Varga et al., 2008). Intriguingly, in aged mice, elevated plasma glucocorticoid levels were associated with an increase in the proportion of suppressor macrophages in spleen (Kizaki et al., 1998), suggesting that endogenous glucocorticoids may regulate macrophage phenotype in vivo, similar to the potent synthetic glucocorticoids used in the in vitro studies. However, further clarification of the macrophage phenotypes involved in both the in vivo and in vitro studies is required before conclusions can be drawn concerning the involvement of glucocorticoids in suppressor macrophage differentiation and function.
8. GR agonists; pharmacological and physiological GR activation
A variety of GR ligands are in use clinically which have different potency and differ in their biological efficacy. Different ligands clearly induce different conformations of GR that have different gene regulatory properties (Croxtall et al., 2002; Elmore et al., 2004) - indeed this has recently been exploited in the search for “dissociated” ligands which dissociate the beneficial anti-inflammatory (repressive) effects of GR agonism from the unwanted metabolic (activation) effects (Schacke et al., 2007; De Bosscher and Haegeman, 2009). Structural studies, including of dexamethasone, fluticasone fuorate and, more recently non-steroidal agonists bound in the GR ligand binding domain have shown that GR readily changes conformation to accommodate large moieties on the ligand and have illustrated new possibilities for mode of ligand binding to GR (Madauss et al., 2008; Biggadike et al., 2009). Thus, different conformations of GR resulting from different ligand associations may have cell-specific and target gene-specific properties that offer potential for future pharmacological exploitation.
8.1. Endogenous glucocorticoid action
Much of the research on the anti-inflammatory and immunosuppressive actions of glucocorticoids has been carried out with saturating levels of synthetic hormones. In humans, these include prednisolone and methylprednisolone, but in animal models and in vitro, dexamethasone is most commonly used. This has provided an over-simplified view of the immunomodulatory actions of glucocorticoids and may have overlooked important opportunities for therapeutic manipulation of endogenous glucocorticoid action. This subject has been previously reviewed (Munck et al., 1984; Wilckens, 1995; Wilckens and De Rijk, 1997; Yeager et al., 2004; Simons, 2008), and the discussion here is restricted to more recent insights.
Synthetic glucocorticoids, especially dexamethasone, have higher affinity, greater bioavailability (unlike the natural hormones, most bind poorly or not at all to corticosteroid binding globulin) and are poorly metabolised, thus they persist in plasma much longer than endogenous glucocorticoids (cortisol, corticosterone). Moreover, the endogenous hormones are released from the adrenal gland in both a circadian and a highly pulsatile (ultradian) manner (reviewed in (Lightman, 2008)). Recent work from the laboratories of Gordon Hager and Stafford Lightman has shown that this pulsatile release of glucocorticoids is coupled to a highly dynamic pattern of GR-mediated transcriptional bursts, driven by rapid recycling of GR occupancy of chromatin binding sites in response to the hormonal pulses in vivo as well as in vitro (Stavreva et al., 2009). This pulsatility did not occur with constant administration of hormone, nor did it happen with synthetic ligands, including dexamethasone, which failed to cause significant ultradian cycling of GR on chromatin and consequently failed to couple fluctuations in hormone levels with transcriptional response (Stavreva et al., 2009). Thus, transcriptional output can be profoundly altered by synthetic GR ligands or even with natural hormones if not administered in the natural pattern (Stavreva et al., 2009). Moreover, basal levels of glucocorticoids in vivo exert tonic effects. Thus, macrophages elicited by thioglycollate in the peritoneum of adrenalectomised rats behaved very differently to macrophages from sham operated rats, with much greater TNFα secretion and NO production in the unstimulated state, which could only be marginally increased by LPS/IFNγ stimulation (Lim et al., 2007). Cytokines themselves are potent activators of the HPA axis (Besedovsky and del Rey, 1996; Webster et al., 2002; Sternberg, 2006), and may permanently programme endogenous glucocorticoid secretion when elevated in early life (Shanks et al., 2000). Importantly, when the HPA axis is activated, not only is plasma cortisol elevated (corticosterone in rodents), but so is plasma cortisone (11-dehydrocorticosterone in rodents), itself intrinsically inert due to poor binding to GR, but which is available in plasma (it shows negligible binding to corticosteroid binding globulin) and which can be readily enzymatically converted inside cells to the active steroid by 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1).
9. 11β-HSD1 amplifies glucocorticoid action within cells
The last 2 decades have produced a wealth of information on the importance of pre-receptor steroid metabolism. By interconverting active glucocorticoids and inert 11-keto metabolites (cortisone, 11-dehydrocorticosterone), 11β-HSD modulates intracellular access of glucocorticoid to receptors. Type 2 11β-HSD (11β-HSD2) inactivates glucocorticoids in vivo, thus protecting the otherwise non-selective MR from occupation by glucocorticoids (Funder, 1997; Seckl, 2000). In contrast, because 11β-HSD1 reactivates glucocorticoids, it increases intracellular glucocorticoid concentration. In addition to cortisone (the natural metabolite), certain synthetic steroids (notably prednisone/prednisolone) are also substrates for the 11β-HSD enzymes. The reaction direction of 11β-HSD1 is dictated by its association with hexose-6-phosphate dehydrogenase (H6PD), which couples glucose-6-phosphate oxidation to NADP reduction, generating NADPH co-factor to drive 11β-HSD1 reductase activity (White et al., 2007; Atanasov et al., 2008). 11β-HSD1 has attracted a lot of recent attention as a potential therapeutic target for metabolic disease, with inhibitors currently under clinical development (Boyle and Kowalski, 2009; Rosenstock et al., 2009). Overexpression of 11β-HSD1 in adipose tissue is associated with obesity in both humans and rodents and in transgenic mice, additionally causes hypertension and insulin resistance (reviewed in Seckl et al. (2004)). Conversely, inhibition of, or deficiency in 11β-HSD1 reduces hyperglycemia and improves insulin sensitivity in non-insulin dependent diabetes in humans and rodents (Seckl et al., 2004). Selective inhibition of 11β-HSD1 also prevented progression of atherosclerosis in Apoe−/− mice and lowered levels of circulating MCP-1, a cytokine that recruits monocytes to sites of injury (Hermanowski-Vosatka et al., 2005). It will be important to determine the extent to which these pro-inflammatory effects of 11β-HSD1 are due to its dysregulation in adipose tissue and possibly other tissues in metabolic disease.
11β-HSD1 is widely expressed, with highest expression in classical glucocorticoid target tissues (Whorwood et al., 1992). Given the crucial immunomodulatory actions of glucocorticoids and the strong association between inflammation and insulin resistance/metabolic disease, the role of 11β-HSD1 in the inflammatory response is of great interest. This area has been recently reviewed (Chapman et al., 2006a,b, 2009; Cooper and Stewart, 2009) and the discussion here is restricted to recent developments and questions.
Like GR, 11β-HSD1 is widely expressed in immune cells, but its expression is highly dependent on the differentiation and activation state of the cell. Circulating leukocytes show little or no 11β-HSD1 expression (Thieringer et al., 2001; Gilmour et al., 2006; Fiore et al., 2009), consistent with negligible 11β-HSD1 activity in monocytes (Thieringer et al., 2001) and low levels in lymphocytes (Hennebold et al., 1996) and neutrophils (Kardon et al., 2008). However, following differentiation of monocytes to macrophages (Thieringer et al., 2001) or dendritic cells (Freeman et al., 2005), 11β-HSD1 activity is dramatically increased and is further increased with polarisation to “M1” pro-inflammatory macrophages compared to “M2” anti-inflammatory macrophages (Martinez et al., 2006). Amplification of endogenous glucocorticoids by 11β-HSD1 may influence macrophage state as thioglycollate-elicited peritoneal macrophages from 11β-HSD1-deficient mice showed increased pro-inflammatory cytokine production following LPS stimulation in vitro, in the absence of added 11β-HSD1 substrate (Gilmour et al., 2006; Zhang and Daynes, 2007) as well as in vivo (Zhang and Daynes, 2007). Interestingly, macrophage 11β-HSD1 is down-regulated following phagocytosis of apoptotic neutrophils; a pro-resolution process (Chapman et al., 2009). The down-regulation of 11β-HSD1 may be part of this mechanism to terminate inflammation. In the absence of 11β-HSD1, mice are more sensitive to endotoxaemia (Zhang and Daynes, 2007), acute inflammation is more severe (Coutinho et al., 2006), and pro-resolution mechanisms may be delayed (Gilmour et al., 2006). We have recently found 11β-HSD1 expression and activity in mast cells, key initiators of acute inflammation and critical targets of the anti-inflammatory actions of glucocorticoids in allergy (Coutinho et al., 2006). Mast cells from 11β-HSD1-deficient mice are hypersensitive to degranulating stimuli (Coutinho et al., 2006), suggesting that endogenous glucocorticoid amplification via 11β-HSD1 restrains their activity. This may be analagous to dendritic cells where it has also been suggested that 11β-HSD1 activity, which is set at high levels in immature dendritic cells and decreases following CD40 activation (a signal that supports cytotoxic T cell differentiation O'Sullivan and Thomas (2002)), may raise the threshold for dendritic cell-induced immune activation, by increasing glucocorticoid action within immature dendritic cells (Freeman et al., 2005).
Within lymphoid cells, 11β-HSD1 activity is present at low levels (Zhang et al., 2005) but is increased following activation of CD4+ T cells through the T cell receptor or following polarisation into Th1 or Th2 cells (Zhang et al., 2005), possibly enhancing the ability of endogenous glucocorticoids to suppress Th1 cytokines (in Th1 cells) as well as sparing or promoting Th2 cytokine production by Th2 cells. Thymocytes also express low levels of 11β-HSD1, which is markedly increased, in parallel with GR levels, by burn injury in mice (D’Elia et al., 2009), a strong stimulus to the HPA axis (Hawes et al., 1995). The increase in 11β-HSD1 activity was associated with an increased rate of thymocyte apoptosis (D’Elia et al., 2009). The same may be true in human lymphocyte precursors. In a recent study in acute lymphoblastic leukaemia (ALL) patients, glucocorticoid treatment increased both 11β-HSD1 and GR mRNA levels in glucocorticoid-sensitive leukaemic cells, but decreased 11β-HSD1 mRNA levels in cells resistant to the pro-apoptotic effects of glucocorticoids (Sai et al., 2009). This combination of increased 11β-HSD1 and GR expression is likely to contribute very significantly to the increased glucocorticoid sensitivity of the leukaemic cells, though whether low 11β-HSD1 and GR expression is a cause or an effect of the glucocorticoid resistance in glucocorticoid-resistant leukaemia remains to be determined.
Of great interest is the relevance of 11β-HSD1 to human inflammatory disease. 11β-HSD1 expression is increased in a cell-specific manner by pro-inflammatory cytokines, particularly IL-1 and TNFα (reviewed Chapman et al. (2006a,b, 2009), Cooper and Stewart (2009)) and at sites of inflammation (Ergang et al., 2007; Zbankova et al., 2007; Ahmed et al., 2008; Hardy et al., 2008; Jang et al., 2009). However, it may be decreased in others. Recent data have shown decreased 11β-HSD1 mRNA levels in lung in a mouse model of tuberculosis (Abbott et al., 2009), where, similar to other inflammatory conditions, 11β-HSD1 shows a reciprocal regulation to 11β-HSD2 (Ergang et al., 2007; Abbott et al., 2009). An even further level of complexity is revealed by the findings that in human rheumatoid arthritis, 11β-HSD1 is increased in synovial fibroblasts, whereas synovial macrophages express 11β-HSD2 (Hardy et al., 2008); suggesting a complex control over glucocorticoid availability within the rheumatic joint. 11β-HSD2 is not normally expressed in macrophages (Thieringer et al., 2001; Gilmour et al., 2006), nor is it expressed here during acute inflammation, at least in mice (Thieringer et al., 2001; Gilmour et al., 2006). However, other groups have also reported 11β-HSD2 expression in rheumatoid arthritis patients in synovial macrophages (Schmidt et al., 2005), immortalised B cells (Haas et al., 2006) and peripheral blood mononuclear cells (Olsen et al., 2004). Whether this is part of an adaptive response to inflammation or contributes to glucocorticoid resistance will be important to establish.
Finally, recent work is starting to elucidate the mechanisms that regulate 11β-HSD1 expression. Whilst the C/EBP family of transcription factors (McKnight, 2001; Nerlov, 2007) was implicated some years ago (Williams et al., 2000), recent data have shown the pivotal role of C/EBPβ in the adipocyte expression and tissue-specific regulation of 11β-HSD1 (Gout et al., 2006; Arai et al., 2007; Payne et al., 2007), and importantly, in mediating the effects of pro-inflammatory mediators on transcription of the gene (Ignatova et al., 2009; Yang et al., 2009b). C/EBPβ has also been implicated in the glucocorticoid-induction of 11β-HSD1 in adipose tissue (Sai et al., 2008), although this may be a tissue-specific mechanism (Sai et al., 2008; Yang et al., 2007). Given that C/EBPβ occupies a pivotal position in the integration of metabolic and inflammatory signals (Hu et al., 2007; Millward et al., 2007; Schroeder-Gloeckler et al., 2007; Cho et al., 2008; Staiger et al., 2008; Du and Ding, 2009; Ito et al., 2009; Ruffell et al., 2009), is a critical component of some glucocorticoid responsive units (e.g. Croniger et al. (1997), Savoldi et al. (1997) and Yamada et al. (1999)) and is also a glucocorticoid target gene itself, being regulated at both mRNA and post-translational levels by glucocorticoids in a tissue-specific manner (Gotoh et al., 1997; Kimura et al., 2001; Penner et al., 2002; Berg et al., 2005; Yang et al., 2005a,b), it will be extremely informative to unravel the associations between C/EBPβ, 11β-HSD1 and glucocorticoids in determination of immune cell differentiation and function.
10. Summary and conclusions
Many aspects of the anti-inflammatory actions of glucocorticoids have not been covered here. However, it is clear that the field is at an exciting stage. The next few years should provide a big step forward in our understanding of how these important hormones exert their effects, with concomitant advances in the clinical treatment of inflammatory disease.
Acknowledgements
Work in the authors’ laboratory is funded by grants from The Medical Research Council and The Wellcome Trust. We thank our colleagues in the Endocrinology Unit and the Centre for Inflammation Research for many stimulating discussions. We apologise to those whose work we have been unable to include or which may inadvertently have escaped our attention.
References
- Abbott A.N., Guidry T.V., Welsh K.J., Thomas A.M., Kling M.A., Hunter R.L., Actor J.K. 11β-Hydroxysteroid Dehydrogenases Are Regulated during the Pulmonary Granulomatous Response to the Mycobacterial Glycolipid Trehalose-6,6’-Dimycolate. Neuroimmunomodulation. 2009;16:147–154. doi: 10.1159/000204227. [DOI] [PubMed] [Google Scholar]
- Abraham S.M., Lawrence T., Kleiman A., Warden P., Medghalchi M., Tuckermann J., Saklatvala J., Clark A.R. Antiinflammatory effects of dexamethasone are partly dependent on induction of dual specificity phosphatase 1. J. Exp. Med. 2006;203:1883–1889. doi: 10.1084/jem.20060336. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Adams M., Meijer O.C., Wang J., Bhargava A., Pearce D. Homodimerization of the glucocorticoid receptor is not essential for response element binding: activation of the phenylethanolamine N-methyltransferase gene by dimerization-defective mutants. Mol. Endocrinol. 2003;17:2583–2592. doi: 10.1210/me.2002-0305. [DOI] [PubMed] [Google Scholar]
- Ahmed A., Saksena S., Sherlock M., Olliff S.P., Elias E., Stewart P.M. Induction of hepatic 11β-hydroxysteroid dehydrogenase type 1 in patients with alcoholic liver disease. Clin. Endocrinol. (Oxf) 2008;68:898–903. doi: 10.1111/j.1365-2265.2007.03125.x. [DOI] [PubMed] [Google Scholar]
- Alam T., An M.R., Mifflin R.C., Hsieh C.-C., Ge X., Papaconstantinou J. Trans-activation of the α1-acid glycoprotein gene acute phase responsive element by multiple isoforms of C/EBP and glucocorticoid receptor. J. Biol. Chem. 1993;268:15681–15688. [PubMed] [Google Scholar]
- Arai N., Masuzaki H., Tanaka T., Ishii T., Yasue S., Kobayashi N., Tomita T., Noguchi M., Kusakabe T., Fujikura J., Ebihara K., Hirata M., Hosoda K., Hayashi T., Sawai H., Minokoshi Y., Nakao K. Ceramide and adenosine 5’-monophosphate-activated protein kinase are two novel regulators of 11β-hydroxysteroid dehydrogenase type 1 expression and activity in cultured preadipocytes. Endocrinology. 2007;148:5268–5277. doi: 10.1210/en.2007-0349. [DOI] [PubMed] [Google Scholar]
- Ashwell J.D., Lu F.W., Vacchio M.S. Glucocorticoids in T cell development and function. Ann. Rev. Immunol. 2000;18:309–345. doi: 10.1146/annurev.immunol.18.1.309. [DOI] [PubMed] [Google Scholar]
- Atanasov A.G., Nashev L.G., Gelman L., Legeza B., Sack R., Portmann R., Odermatt A. Direct protein-protein interaction of 11β-hydroxysteroid dehydrogenase type 1 and hexose-6-phosphate dehydrogenase in the endoplasmic reticulum lumen. Biochim. Biophys. Acta. 2008;1783:1536–1543. doi: 10.1016/j.bbamcr.2008.03.001. [DOI] [PubMed] [Google Scholar]
- Auphan N., DiDonato J.A., Rosette C., Helmberg A., Karin M. Immunosupression by glucocorticoids: inhibition of NF-κB activity through induction of IκB synthesis. Science. 1995;270:286–290. doi: 10.1126/science.270.5234.286. [DOI] [PubMed] [Google Scholar]
- Ayroldi E., Riccardi C. Glucocorticoid-induced leucine zipper (GILZ): a new important mediator of glucocorticoid action. FASEB J. 2009;23:3649–3658. doi: 10.1096/fj.09-134684. [DOI] [PubMed] [Google Scholar]
- Barish G.D., Downes M., Alaynick W.A., Yu R.T., Ocampo C.B., Bookout A.L., Mangelsdorf D.J., Evans R.M. A Nuclear Receptor Atlas: macrophage activation. Mol. Endocrinol. 2005;19:2466–2477. doi: 10.1210/me.2004-0529. [DOI] [PubMed] [Google Scholar]
- Barnes P.J. Anti-inflammatory actions of glucocorticoids: molecular mechanisms. Clin. Sci. (Lond) 1998;94:557–572. doi: 10.1042/cs0940557. [DOI] [PubMed] [Google Scholar]
- Beato M., Chalepakis G., Schauer M., Slater E.P. DNA regulatory elements for steroid hormones. J. Steroid Biochem. 1989;32:737–748. doi: 10.1016/0022-4731(89)90521-9. [DOI] [PubMed] [Google Scholar]
- Beato M., Chavez S., Truss M. Transcriptional regulation by steroid hormones. Steroids. 1996;61:240–251. doi: 10.1016/0039-128x(96)00030-x. [DOI] [PubMed] [Google Scholar]
- Berg T., Didon L., Barton J., Andersson O., Nord M. Glucocorticoids increase C/EBPβ activity in the lung epithelium via phosphorylation. Biochem. Biophys. Res. Commun. 2005;334:638–645. doi: 10.1016/j.bbrc.2005.06.146. [DOI] [PubMed] [Google Scholar]
- Bertini R., Bianchi M., Ghezzi P. Adrenalectomy sensitizes mice to the lethal effects of Interleukin-1 and Tumor Necrosis Factor. J. Exp. Med. 1988;167:1708–1712. doi: 10.1084/jem.167.5.1708. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Besedovsky H.O., del Rey A. Immune-neuro-endocrine interactions: facts and hypotheses. Endocr. Rev. 1996;17:64–102. doi: 10.1210/edrv-17-1-64. [DOI] [PubMed] [Google Scholar]
- Bhattacharyya S., Brown D.E., Brewer J.A., Vogt S.K., Muglia L.J. Macrophage glucocorticoid receptors regulate Toll-like receptor-4-mediated inflammatory responses by selective inhibition of p38 MAP kinase. Blood. 2007;109:4313–4319. doi: 10.1182/blood-2006-10-048215. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Biddie S.C., Hager G.L. Glucocorticoid receptor dynamics and gene regulation. Stress. 2009;12:193–205. doi: 10.1080/10253890802506409. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Biggadike K., Bledsoe R.K., Coe D.M., Cooper T.W., House D., Iannone M.A., Macdonald S.J., Madauss K.P., McLay I.M., Shipley T.J., Taylor S.J., Tran T.B., Uings I.J., Weller V., Williams S.P. Design and X-ray crystal structures of high-potency nonsteroidal glucocorticoid agonists exploiting a novel binding site on the receptor. Proc. Natl. Acad. Sci. U.S.A. 2009;106:18114–18119. doi: 10.1073/pnas.0909125106. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Blind R.D., Garabedian M.J. Differential recruitment of glucocorticoid receptor phospho-isoforms to glucocorticoid-induced genes. J. Steroid Biochem. Mol. Biol. 2008;109:150–157. doi: 10.1016/j.jsbmb.2008.01.002. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Bommhardt U., Beyer M., Hunig T., Reichardt H.M. Molecular and cellular mechanisms of T cell development. Cell. Mol. Life Sci. 2004;61:263–280. doi: 10.1007/s00018-003-3224-3. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Boyle C.D., Kowalski T.J. 11β-hydroxysteroid dehydrogenase type 1 inhibitors: a review of recent patents. Expert Opin. Ther. Pat. 2009;19:801–825. doi: 10.1517/13543770902967658. [DOI] [PubMed] [Google Scholar]
- Brewer J.A., Kanagawa O., Sleckman B.P., Muglia L.J. Thymocyte apoptosis induced by T cell activation is mediated by glucocorticoids in vivo. J. Immunol. 2002;169:1837–1843. doi: 10.4049/jimmunol.169.4.1837. [DOI] [PubMed] [Google Scholar]
- Brewer J.A., Khor B., Vogt S.K., Muglia L.M., Fujiwara H., Haegele K.E., Sleckman B.P., Muglia L.J. T-cell glucocorticoid receptor is required to suppress COX-2-mediated lethal immune activation. Nat. Med. 2003;9:1318–1322. doi: 10.1038/nm895. [DOI] [PubMed] [Google Scholar]
- Cannarile L., Cuzzocrea S., Santucci L., Agostini M., Mazzon E., Esposito E., Muia C., Coppo M., Di Paola R., Riccardi C. Glucocorticoid-induced leucine zipper is protective in Th1-mediated models of colitis. Gastroenterology. 2009;136:530–541. doi: 10.1053/j.gastro.2008.09.024. [DOI] [PubMed] [Google Scholar]
- Cannarile L., Fallarino F., Agostini M., Cuzzocrea S., Mazzon E., Vacca C., Genovese T., Migliorati G., Ayroldi E., Riccardi C. Increased GILZ expression in transgenic mice up-regulates Th-2 lymphokines. Blood. 2006;107:1039–1047. doi: 10.1182/blood-2005-05-2183. [DOI] [PubMed] [Google Scholar]
- Chamorro S., Garcia-Vallejo J.J., Unger W.W., Fernandes R.J., Bruijns S.C., Laban S., Roep B.O., t Hart B.A., van Kooyk Y. TLR triggering on tolerogenic dendritic cells results in TLR2 up-regulation and a reduced proinflammatory immune program. J. Immunol. 2009;183:2984–2994. doi: 10.4049/jimmunol.0801155. [DOI] [PubMed] [Google Scholar]
- Chapman K.E., Coutinho A., Gray M., Gilmour J.S., Savill J.S., Seckl J.R. Local amplification of glucocorticoids by 11β-hydroxysteroid dehydrogenase type 1 and its role in the inflammatory response. Ann. N.Y. Acad. Sci. 2006;1088:265–273. doi: 10.1196/annals.1366.030. [DOI] [PubMed] [Google Scholar]
- Chapman K.E., Coutinho A.E., Gray M., Gilmour J.S., Savill J.S., Seckl J.R. The role and regulation of 11β-hydroxysteroid dehydrogenase type 1 in the inflammatory response. Mol. Cell. Endocrinol. 2009;301:123–131. doi: 10.1016/j.mce.2008.09.031. [DOI] [PubMed] [Google Scholar]
- Chapman K.E., Gilmour J.S., Coutinho A.E., Savill J.S., Seckl J.R. 11β-hydroxysteroid dehydrogenase type 1- a role in inflammation? Mol. Cell Endocrinol. 2006;248:3–8. doi: 10.1016/j.mce.2005.11.036. [DOI] [PubMed] [Google Scholar]
- Cho I.J., Woo N.R., Kim S.G. The identification of C/EBPβ as a transcription factor necessary for the induction of MAPK phosphatase-1 by toll-like receptor-4 ligand. Arch. Biochem. Biophys. 2008;479:88–96. doi: 10.1016/j.abb.2008.08.007. [DOI] [PubMed] [Google Scholar]
- Clark A.R. Anti-inflammatory functions of glucocorticoid-induced genes. Mol. Cell. Endocrinol. 2007;275:79–97. doi: 10.1016/j.mce.2007.04.013. [DOI] [PubMed] [Google Scholar]
- Clausen B.E., Burkhardt C., Reith W., Renkawitz R., Forster I. Conditional gene targeting in macrophages and granulocytes using LysMcre mice. Transgenic Res. 1999;8:265–277. doi: 10.1023/a:1008942828960. [DOI] [PubMed] [Google Scholar]
- Cohen N., Mouly E., Hamdi H., Maillot M.-C., Pallardy M., Godot V., Capel F., Balian A., Naveau S., Galanaud P., Lemoine F.M., Emilie D. GILZ expression in human dendritic cells redirects their maturation and prevents antigen-specific T lymphocyte response. Blood. 2006;107:2037–2044. doi: 10.1182/blood-2005-07-2760. [DOI] [PubMed] [Google Scholar]
- Cole T., Blendy J.A., Monaghan A.P., Kriegelstein K., Schmid W., Fantuzzi G., Hummler E., Unsicker K., Schütz G. Targeted disruption of the glucocorticoid receptor blocks adrenergic chromaffin cell development and severely retards lung maturation. Genes Dev. 1995;9:1608–1621. doi: 10.1101/gad.9.13.1608. [DOI] [PubMed] [Google Scholar]
- Cole T.J., Myles K., Purton J.F., Brereton P.S., Solomon N.M., Godfrey D.I., Funder J.W. GRKO mice express an aberrant dexamethasone-binding glucocorticoid receptor, but are profoundly glucocorticoid resistant. Mol. Cell. Endocrinol. 2001;173:193–202. doi: 10.1016/s0303-7207(00)00407-x. [DOI] [PubMed] [Google Scholar]
- Cooper M.S., Stewart P.M. 11β-Hydroxysteroid dehydrogenase type 1 and its role in the hypothalamus-pituitary-adrenal axis, metabolic syndrome, and inflammation. J. Clin. Endocrinol. Metab. 2009;(October (16)) doi: 10.1210/jc.2009-1412. Epub ahead of print. [DOI] [PubMed] [Google Scholar]
- Couper K.N., Blount D.G., Riley E.M. IL-10: the master regulator of immunity to infection. J. Immunol. 2008;180:5771–5777. doi: 10.4049/jimmunol.180.9.5771. [DOI] [PubMed] [Google Scholar]
- Coutinho A.E., Gray M., Sawatzky D.A., Brownstein D., Gilmour J.S., Mullins J., Seckl J.R., Savill J.S., Chapman K.E. Abstracts of the 88th meeting of the American Endocrine Society. 2006. Deficiency in 11β-hydroxysteroid dehydrogenase type 1 results in a more rapid and severe inflammation; pp. 2–108. [Google Scholar]
- Croniger C., Trus M., Lysek-Stupp K., Cohen H., Liu Y., Darlington G.J., Poli V., Hanson R.W., Reshef L. Role of the isoforms of CCAAT/enhancer-binding protein in the initiation of phosphoenolpyruvate carboxykinase (GTP) gene transcription at birth. J. Biol. Chem. 1997;272:26306–26312. doi: 10.1074/jbc.272.42.26306. [DOI] [PubMed] [Google Scholar]
- Croxtall J.D., van Hal P.T., Choudhury Q., Gilroy D.W., Flower R.J. Different glucocorticoids vary in their genomic and non-genomic mechanism of action in A549 cells. Br. J. Pharmacol. 2002;135:511–519. doi: 10.1038/sj.bjp.0704474. [DOI] [PMC free article] [PubMed] [Google Scholar]
- D’Acquisto F., Merghani A., Lecona E., Rosignoli G., Raza K., Buckley C.D., Flower R.J., Perretti M. Annexin-1 modulates T-cell activation and differentiation. Blood. 2007;109:1095–1102. doi: 10.1182/blood-2006-05-022798. [DOI] [PMC free article] [PubMed] [Google Scholar]
- D’Acquisto F., Paschalidis N., Raza K., Buckley C.D., Flower R.J., Perretti M. Glucocorticoid treatment inhibits annexin-1 expression in rheumatoid arthritis CD4+ T cells. Rheumatology (Oxford) 2008;47:636–639. doi: 10.1093/rheumatology/ken062. [DOI] [PubMed] [Google Scholar]
- D’Acquisto F., Paschalidis N., Sampaio A.L., Merghani A., Flower R.J., Perretti M. Impaired T cell activation and increased Th2 lineage commitment in Annexin-1-deficient T cells. Eur. J. Immunol. 2007;37:3131–3142. doi: 10.1002/eji.200636792. [DOI] [PubMed] [Google Scholar]
- D’Elia M., Patenaude J., Bernier J. Regulation of glucocorticoid sensitivity in thymocytes from burn-injured mice. Am. J. Physiol. Endocrinol. Metab. 2009;296:E97–E104. doi: 10.1152/ajpendo.90582.2008. [DOI] [PubMed] [Google Scholar]
- De Bosscher K., Haegeman G. Latest perspectives on anti-inflammatory actions of glucocorticoids. Mol. Endocrinol. 2009;23:281–291. doi: 10.1210/me.2008-0283. [DOI] [PMC free article] [PubMed] [Google Scholar]
- de Vries F., Pouwels S., Lammers J.W., Leufkens H.G., Bracke M., CooperF C., van Staa T.P. Use of inhaled and oral glucocorticoids, severity of inflammatory disease and risk of hip/femur fracture: a population-based case-control study. J. Intern. Med. 2007;261:170–177. doi: 10.1111/j.1365-2796.2006.01754.x. [DOI] [PubMed] [Google Scholar]
- Delfino D.V., Agostini M., Spinicelli S., Vacca C., Riccardi C. Inhibited cell death, NF-|B activity and increased IL-10 in TCR-triggered thymocytes of transgenic mice overexpressing the glucocorticoid-induced protein GILZ. Int. Immunopharmacol. 2006;6:1126–1134. doi: 10.1016/j.intimp.2006.02.001. [DOI] [PubMed] [Google Scholar]
- Du K., Ding J. Insulin Regulates TRB3 and Other Stress Responsive Gene Expression through Induction of C/EBPβ. Mol. Endocrinol. 2009;23:475–485. doi: 10.1210/me.2008-0284. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Ehrchen J., Steinmuller L., Barczyk K., Tenbrock K., Nacken W., Eisenacher M., Nordhues U., Sorg C., Sunderkotter C., Roth J. Glucocorticoids induce differentiation of a specifically activated, anti-inflammatory subtype of human monocytes. Blood. 2007;109:1265–1274. doi: 10.1182/blood-2006-02-001115. [DOI] [PubMed] [Google Scholar]
- Elmore S.W., Pratt J.K., Coghlan M.J., Mao Y., Green B.E., Anderson D.D., Stashko M.A., Lin C.W., Falls D., Nakane M., Miller L., Tyree C.M., Miner J.N., Lane B. Differentiation of in vitro transcriptional repression and activation profiles of selective glucocorticoid modulators. Bioorg. Med. Chem. Lett. 2004;14:1721–1727. doi: 10.1016/j.bmcl.2004.01.044. [DOI] [PubMed] [Google Scholar]
- Ergang P., Leden P., Bryndova J., Zbankova S., Miksik I., Kment M., Pacha J. Glucocorticoid availability in colonic inflammation of rat. Dig. Dis. Sci. 2007;53:2160–2167. doi: 10.1007/s10620-007-0125-6. [DOI] [PubMed] [Google Scholar]
- Fadok V.A., Bratton D.L., Konowal A., Freed P.W., Westcott J.Y., Henson P.M. Macrophages that have ingested apoptotic cells in vitro inhibit proinflammatory cytokine production through autocrine/paracrine mechanisms involving TGF-βPGE2, and PAF. J. Clin. Invest. 1998;101:890–898. doi: 10.1172/JCI1112. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Finotto S., Krieglstein K., Schober A., Deimling F., Lindner K., Bruhl B., Beier K., Metz J., GarciaArraras J.E., RoigLopez J.L., Monaghan P., Schmid W., Cole T.J., Kellendonk C., Tronche F., Schutz G., Unsicker K. Analysis of mice carrying targeted mutations of the glucocorticoid receptor gene argues against an essential role of glucocorticoid signalling for generating adrenal chromaffin cells. Development. 1999;126:2935–2944. doi: 10.1242/dev.126.13.2935. [DOI] [PubMed] [Google Scholar]
- Fiore C., Nardi A., Dalla Valle L., Pellati D., Krozowski Z., Colombo L., Armanini D. Identification of the 11β-hydroxysteroid dehydrogenase type 1 mRNA and protein in human mononuclear leukocytes. Exp. Clin. Endocrinol. Diabetes. 2009;117:514–518. doi: 10.1055/s-0028-1105924. [DOI] [PubMed] [Google Scholar]
- Frank M.G., Miguel Z.D., Watkins L.R., Maier S.F. Prior exposure to glucocorticoids sensitizes the neuroinflammatory and peripheral inflammatory responses to E. coli lipopolysaccharide. Brain Behav. Immun. 2010;24:19–30. doi: 10.1016/j.bbi.2009.07.008. [DOI] [PubMed] [Google Scholar]
- Freeman L., Hewison M., Hughes S.V., Evans K.N., Hardie D., Means T.K., Chakraverty R. Expression of 11β-hydroxysteroid dehydrogenase type 1 permits regulation of glucocorticoid bioavailability by human dendritic cells. Blood. 2005;106:2042–2049. doi: 10.1182/blood-2005-01-0186. [DOI] [PubMed] [Google Scholar]
- Funder J.W. Glucocorticoid and mineralocorticoid receptors: Biology and clinical relevance. Annu. Rev. Med. 1997;48:231–240. doi: 10.1146/annurev.med.48.1.231. [DOI] [PubMed] [Google Scholar]
- Giles K.M., Ross K., Rossi A.G., Hotchin N.A., Haslett C., Dransfield I. Glucocorticoid augmentation of macrophage capacity for phagocytosis of apoptotic cells is associated with reduced p130Cas expression, loss of paxillin/pyk2 phosphorylation, and high levels of active Rac. J. Immunol. 2001;167:976–986. doi: 10.4049/jimmunol.167.2.976. [DOI] [PubMed] [Google Scholar]
- Gilmour J.S., Coutinho A.E., Cailhier J.F., Man T.Y., Clay M., Thomas G., Harris H.J., Mullins J.J., Seckl J.R., Savill J.S., Chapman K.E. Local amplification of glucocorticoids by 11β-hydroxysteroid dehydrogenase type 1 promotes macrophage phagocytosis of apoptotic leukocytes. J. Immunol. 2006;176:7605–7611. doi: 10.4049/jimmunol.176.12.7605. [DOI] [PubMed] [Google Scholar]
- Gilroy D.W. The endogenous control of acute inflammation - from onset to resolution. Drug Discov. Today: Therap. Strategies. 2004;1:313. [Google Scholar]
- Godfrey D.I., Purton J.F., Boyd R.L., Cole T.J. Glucocorticoids and the thymus: the view from the middle of the road. Trends Immunol. 2001;22:243. doi: 10.1016/s1471-4906(01)01916-0. [DOI] [PubMed] [Google Scholar]
- Gotoh T., Chowdhury S., Takiguchi M., Mori M. The glucocorticoid-responsive gene cascade: activation of the rat arginase gene through induction of C/EBPβ. J. Biol. Chem. 1997;272:3694–3698. doi: 10.1074/jbc.272.6.3694. [DOI] [PubMed] [Google Scholar]
- Goulding N.J., Godolphin J.L., Sampson M.B., Maddison P.J., Flower R.J. Hydrocortisone induces lipocortin 1 production by peripheral blood mononuclear cells in vivo in man. Biochem. Soc. Trans. 1990;18:306–307. doi: 10.1042/bst0180306. [DOI] [PubMed] [Google Scholar]
- Gout J., Tirard J., Thevenon C., Riou J.P., Begeot M., Naville D. CCAAT/enhancer-binding proteins (C/EBPs) regulate the basal and cAMP-induced transcription of the human 11β-hydroxysteroid dehydrogenase encoding gene in adipose cells. Biochimie. 2006;88:1115–1124. doi: 10.1016/j.biochi.2006.05.020. [DOI] [PubMed] [Google Scholar]
- Grange T., Cappabianca L., Flavin M., Sassi H., Thomassin H. In vivo analysis of the model tyrosine aminotransferase gene reveals multiple sequential steps in glucocorticoid receptor action. Oncogene. 2001;20:3028–3038. doi: 10.1038/sj.onc.1204327. [DOI] [PubMed] [Google Scholar]
- Grange T., Roux J., Rigaud G., Pictet R. Two remote glucocorticoid responsive units interact cooperatively to promote glucocorticoid induction of rat tyrosine aminotransferase gene expression. Nucl. Acids Res. 1989;17:8695–8709. doi: 10.1093/nar/17.21.8695. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Grange T., Roux J., Rigaud G., Pictet R. Cell-type specific activity of two glucocorticoid responsive units of rat tyrosine aminotransferase gene is associated with multiple binding sites for C/EBP and a novel liver-specific nuclear factor. Nucl. Acids Res. 1991;19:131–139. doi: 10.1093/nar/19.1.131. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Haas C.S., Creighton C.J., Pi X., Maine I., Koch A.E., Haines G.K., Ling S., Chinnaiyan A.M., Holoshitz J. Identification of genes modulated in rheumatoid arthritis using complementary DNA microarray analysis of lymphoblastoid B cell lines from disease-discordant monozygotic twins. Arthritis Rheum. 2006;54:2047–2060. doi: 10.1002/art.21953. [DOI] [PubMed] [Google Scholar]
- Hager G.L., Nagaich A.K., Johnson T.A., Walker D.A., John S. Dynamics of nuclear receptor movement and transcription. Biochim. Biophys. Acta. 2004;1677:46–51. doi: 10.1016/j.bbaexp.2003.09.016. [DOI] [PubMed] [Google Scholar]
- Hamdi H., Godot V., Maillot M.C., Prejean M.V., Cohen N., Krzysiek R., Lemoine F.M., Zou W., Emilie D. Induction of antigen-specific regulatory T lymphocytes by human dendritic cells expressing the glucocorticoid-induced leucine zipper. Blood. 2007;110:211–219. doi: 10.1182/blood-2007-08-107896. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Hammer M., Mages J., Dietrich H., Servatius A., Howells N., Cato A.C., Lang R. Dual specificity phosphatase 1 (DUSP1) regulates a subset of LPS-induced genes and protects mice from lethal endotoxin shock. J. Exp. Med. 2006;203:15–20. doi: 10.1084/jem.20051753. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Hannon R., Croxtall J.D., Getting S.J., Roviezzo F., Yona S., Paul-Clark M.J., Gavins F.N., Perretti M., Morris J.F., Buckingham J.C., Flower R.J. Aberrant inflammation and resistance to glucocorticoids in annexin 1−/− mouse. FASEB J. 2003;17:253–255. doi: 10.1096/fj.02-0239fje. [DOI] [PubMed] [Google Scholar]
- Härd T., Kellenbach E., Boelens R., Maler B.A., Dahlman K., Freedman L.P., Carlstedt-Duke J., Yamamoto K.R., Gustafsson J.-Å. Solution structure of the glucocorticoid receptor DNA-binding domain. Science. 1990;249:157–160. doi: 10.1126/science.2115209. [DOI] [PubMed] [Google Scholar]
- Hardy R.S., Rabbitt E.H., Filer A., Emery P., Hewison M., Stewart P.M., Gittoes N., Buckley C.D., Raza K., Cooper M.S. Local and systemic glucocorticoid metabolism in inflammatory arthritis. Ann. Rheum. Dis. 2008;67:1204–1210. doi: 10.1136/ard.2008.090662. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Harizi H., Mormede P., Corcuff J.B. Inter-strain differences in glucocorticoid and mineralocorticoid effects on macrophage and lymphocyte functions in mice. J. Neuroimmunol. 2008;204:38–42. doi: 10.1016/j.jneuroim.2008.08.004. [DOI] [PubMed] [Google Scholar]
- Haslett C., Lee A., Savill J.S., Meagher L., Whyte M.K. Apoptosis (programmed cell death) and functional changes in aging neutrophils: modulation by inflammatory mediators. Chest. 1991;99:6S. [PubMed] [Google Scholar]
- Hawes A.S., Richardson R.P., Antonacci A.C., Calvano S.E. Chronic pathophysiologic elevation of corticosterone after thermal injury or thermal injury and burn wound infection adversely affects body mass, lymphocyte numbers, and outcome. J. Burn Care Rehabil. 1995;16:1–15. doi: 10.1097/00004630-199501000-00002. [DOI] [PubMed] [Google Scholar]
- Hawrylowicz C.M. Regulatory T cells and IL-10 in allergic inflammation. J. Exp. Med. 2005;202:1459–1463. doi: 10.1084/jem.20052211. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Heasman S.J., Giles K.M., Ward C., Rossi A.G., Haslett C., Dransfield I. Glucocorticoid-mediated regulation of granulocyte apoptosis and macrophage phagocytosis of apoptotic cells: implications for the resolution of inflammation. J. Endocrinol. 2003;178:29–36. doi: 10.1677/joe.0.1780029. [DOI] [PubMed] [Google Scholar]
- Heck S., Bender K., Kullmann M., Gottlicher M., Herrlich P., Cato A.C. IκBα-independent downregulation of NF-κB activity by glucocorticoid receptor. EMBO J. 1997;16:4698–4707. doi: 10.1093/emboj/16.15.4698. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Heck S., Kullmann M., Gast A., Ponta H., Rahmsdorf H.J., Herrlich P., Cato A.C.B. A distinct modulating domain in glucocorticoid receptor monomers in the repression of activity of the transcription factor AP-1. EMBO J. 1994;13:4087–4095. doi: 10.1002/j.1460-2075.1994.tb06726.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Hennebold J.D., Ryu S.Y., Mu H.H., Galbraith A., Daynes R.A. 11β-hydroxysteroid dehydrogenase modulation of glucocorticoid activities in lymphoid organs. Am. J. Physiol. 1996;270:R1296–1306. doi: 10.1152/ajpregu.1996.270.6.R1296. [DOI] [PubMed] [Google Scholar]
- Hermanowski-Vosatka A., Balkovec J.M., Cheng K., Chen H.Y., Hernandez M., Koo G.C., Le Grand C.B., Li Z., Metzger J.M., Mundt S.S., Noonan H., Nunes C.N., Olson S.H., Pikounis B., Ren N., Robertson N., Schaeffer J.M., Shah K., Springer M.S., Strack A.M., Strowski M., Wu K., Wu T., Xiao J., Zhang B.B., Wright S.D., Thieringer R. 11®-HSD1 inhibition ameliorates metabolic syndrome and prevents progression of atherosclerosis in mice. J. Exp. Med. 2005;202:517–527. doi: 10.1084/jem.20050119. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Herold M.J., McPherson K.G., Reichardt H.M. Glucocorticoids in T cell apoptosis and function. Cell. Mol. Life Sci. 2006;63:60–72. doi: 10.1007/s00018-005-5390-y. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Hollenberg S.M., Weinberger C., Ong E.S., Cerelli G., Oro A., Lebo R., Thompson E.B., Rosenfeld M.G., Evans R.M. Primary structure and expression of a functional human glucocorticoid receptor cDNA. Nature. 1985;318:635–641. doi: 10.1038/318635a0. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Horie-Inoue K., Takayama K., Bono H.U., Ouchi Y., Okazaki Y., Inoue S. Identification of novel steroid target genes through the combination of bioinformatics and functional analysis of hormone response elements. Biochem. Biophys. Res. Commun. 2006;339:99–106. doi: 10.1016/j.bbrc.2005.10.188. [DOI] [PubMed] [Google Scholar]
- Hu B., Ullenbruch M.R., Jin H., Gharaee-Kermani M., Phan S.H. An essential role for CCAAT/enhancer binding protein β in bleomycin-induced pulmonary fibrosis. J. Pathol. 2007;211:455–462. doi: 10.1002/path.2119. [DOI] [PubMed] [Google Scholar]
- Huggins A., Paschalidis N., Flower R.J., Perretti M., D’Acquisto F. Annexin-1-deficient dendritic cells acquire a mature phenotype during differentiation. Faseb J. 2009;23:985–996. doi: 10.1096/fj.08-119040. [DOI] [PubMed] [Google Scholar]
- Ignatova I.D., Kostadinova R.M., Goldring C.E., Nawrocki A.R., Frey F.J., Frey B.M. Tumor necrosis factor-〈 upregulates 11β-hydroxysteroid dehydrogenase type 1 expression by CCAAT/enhancer binding protein-β in HepG2 cells. Am. J. Physiol. Endocrinol. Metab. 2009;296:E367–377. doi: 10.1152/ajpendo.90531.2008. [DOI] [PubMed] [Google Scholar]
- Imai E., Stromstedt P.E., Quinn P.G., Carlstedtduke J., Gustafsson J.A., Granner D.K. Characterization of a complex glucocorticoid response unit in the phosphoenolpyruvate carboxykinase gene. Mol. Cell. Biol. 1990;10:4712–4719. doi: 10.1128/mcb.10.9.4712. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Ito Y., Daitoku H., Fukamizu A. Foxo1 increases pro-inflammatory gene expression by inducing C/EBPβ in TNFα-treated adipocytes. Biochem. Biophys. Res. Commun. 2009;378:290–295. doi: 10.1016/j.bbrc.2008.11.043. [DOI] [PubMed] [Google Scholar]
- Jaffe H.L. The influence of the suprarenal gland on the thymus. J. Exp. Med., XL. 1924:325–343. doi: 10.1084/jem.40.3.325. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Jang C., Obeyesekere V.R., Alford F.P., Inder W.J. Skeletal muscle 11β-hydroxysteroid dehydrogenase type 1 activity is upregulated following elective abdominal surgery. Eur. J. Endocrinol. 2009;160:249–255. doi: 10.1530/EJE-08-0619. [DOI] [PubMed] [Google Scholar]
- Johansson Haque K., Palanichamy E., Okret S. Stimulation of MAPK-phospatase 1 (MKP-1) gene expression by glucocorticoids occurs through a tethering mechanism involving C/EBP. J. Mol. Endocrinol. 2008;41:239–249. doi: 10.1677/JME-08-0015. [DOI] [PubMed] [Google Scholar]
- John S., Johnson T.A., Sung M.H., Biddie S.C., Trump S., Koch-Paiz C.A., Davis S.R., Walker R., Meltzer P.S., Hager G.L. Kinetic complexity of the global response to glucocorticoid receptor action. Endocrinology. 2009;150:1766–1774. doi: 10.1210/en.2008-0863. [DOI] [PMC free article] [PubMed] [Google Scholar]
- John S., Sabo P.J., Johnson T.A., Sung M.H., Biddie S.C., Lightman S.L., Voss T.C., Davis S.R., Meltzer P.S., Stamatoyannopoulos J.A., Hager G.L. Interaction of the glucocorticoid receptor with the chromatin landscape. Mol. Cell. 2008;29:611–624. doi: 10.1016/j.molcel.2008.02.010. [DOI] [PubMed] [Google Scholar]
- Jonat C., Rahmsdorf H.J., Park K.K., Cato A.C.B., Gebel S., Ponta H., Herrlich P. Antitumor promotion and antiinflammation: down-modulation of AP-1 (Fos Jun) activity by glucocorticoid hormone. Cell. 1990;62:1189–1204. doi: 10.1016/0092-8674(90)90395-u. [DOI] [PubMed] [Google Scholar]
- Jondal M., Pazirandeh A., Okret S. Different roles for glucocorticoids in thymocyte homeostasis? Trends Immunol. 2004;25:595–600. doi: 10.1016/j.it.2004.09.003. [DOI] [PubMed] [Google Scholar]
- Kardon T., Senesi S., Marcolongo P., Legeza B., Banhegyi G., Mandl J., Fulceri R., Benedetti A. Maintenance of luminal NADPH in the endoplasmic reticulum promotes the survival of human neutrophil granulocytes. FEBS Lett. 2008;582:1809–1815. doi: 10.1016/j.febslet.2008.04.045. [DOI] [PubMed] [Google Scholar]
- Karin M. New twists in gene regulation by glucocorticoid receptor: Is DNA binding dispensable? Cell. 1998;93:487–490. doi: 10.1016/s0092-8674(00)81177-0. [DOI] [PubMed] [Google Scholar]
- Kassel O., Cato A.C. Mast cells as targets for glucocorticoids in the treatment of allergic disorders. Ernst Schering Res. Found Workshop. 2002:153–176. doi: 10.1007/978-3-662-04660-9_10. [DOI] [PubMed] [Google Scholar]
- Kimura T., Chowdhury S., Tanaka T., Shimizu A., Iwase K., Oyadomari S., Gotoh T., Matsuzaki H., Mori M., Akira S., Takiguchi M. CCAAT/enhancer-binding protein β is required for activation of genes for ornithine cycle enzymes by glucocorticoids and glucagon in primary- cultured hepatocytes. FEBS Lett. 2001;494:105–111. doi: 10.1016/s0014-5793(01)02320-1. [DOI] [PubMed] [Google Scholar]
- King L.B., Vacchio M.S., Dixon K., Hunziker R., Margulies D.H., Ashwell J.D. A targeted glucocorticoid receptor antisense transgene increases thymocyte apoptosis and alters thymocyte development. Immunity. 1995;3:647–656. doi: 10.1016/1074-7613(95)90135-3. [DOI] [PubMed] [Google Scholar]
- Kizaki T., Ookawara T., Oh-Ishi S., Itoh Y., Iwabuchi K., Onoe K., Day N.K., Good R.A., Ohno H. An increase in basal glucocorticoid concentration with age induces suppressor macrophages with high-density Fc gamma RII/III. Immunology. 1998;93:409–414. doi: 10.1046/j.1365-2567.1998.00433.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Kleiman A., Tuckermann J.P. Glucocorticoid receptor action in beneficial and side effects of steroid therapy: lessons from conditional knockout mice. Mol. Cell. Endocrinol. 2007;275:98–108. doi: 10.1016/j.mce.2007.05.009. [DOI] [PubMed] [Google Scholar]
- Koldzic-Zivanovic N., Tu H., Juelich T.L., Rady P.L., Tyring S.K., Hudnall S.D., Smith E.M., Hughes T.K. Regulation of adrenal glucocorticoid synthesis by interleukin-10: a preponderance of IL-10 receptor in the adrenal zona fasciculata. Brain Behav. Immun. 2006;20:460–468. doi: 10.1016/j.bbi.2005.09.003. [DOI] [PubMed] [Google Scholar]
- Kuhn R., Lohler J., Rennick D., Rajewsky K., Muller W. Interleukin-10-deficient mice develop chronic enterocolitis. Cell. 1993;75:263–274. doi: 10.1016/0092-8674(93)80068-p. [DOI] [PubMed] [Google Scholar]
- Lacy-Hulbert A., Smith A.M., Tissire H., Barry M., Crowley D., Bronson R.T., Roes J.T., Savill J.S., Hynes R.O. Ulcerative colitis and autoimmunity induced by loss of myeloid alphav integrins. Proc. Natl. Acad. Sci. U.S.A. 2007;104:15823–15828. doi: 10.1073/pnas.0707421104. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Lefstin J.A., Yamamoto K.R. Allosteric effects of DNA on transcriptional regulators. Nature. 1998;392:885–888. doi: 10.1038/31860. [DOI] [PubMed] [Google Scholar]
- Lightman S.L. The neuroendocrinology of stress: a never ending story. J. Neuroendocrinol. 2008;20:880–884. doi: 10.1111/j.1365-2826.2008.01711.x. [DOI] [PubMed] [Google Scholar]
- Lim H.Y., Muller N., Herold M.J., van den Brandt J., Reichardt H.M. Glucocorticoids exert opposing effects on macrophage function dependent on their concentration. Immunology. 2007;122:47–53. doi: 10.1111/j.1365-2567.2007.02611.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Limbourg F.P., Huang Z., Plumier J.C., Simoncini T., Fujioka M., Tuckermann J., Schutz G., Moskowitz M.A., Liao J.K. Rapid nontranscriptional activation of endothelial nitric oxide synthase mediates increased cerebral blood flow and stroke protection by corticosteroids. J. Clin. Invest. 2002;110:1729–1738. doi: 10.1172/JCI15481. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Lu F.W., Yasutomo K., Goodman G.B., McHeyzer-Williams L.J., McHeyzer-Williams M.G., Germain R.N., Ashwell J.D. Thymocyte resistance to glucocorticoids leads to antigen-specific unresponsiveness due to “holes” in the T cell repertoire. Immunity. 2000;12:183–192. doi: 10.1016/s1074-7613(00)80171-5. [DOI] [PubMed] [Google Scholar]
- Luisi B.F., Xu W.X., Otwinowski Z., Freedman L.P., Yamamoto K.R., Sigler P.B. Crystallographic analysis of the interaction of the glucocorticoid receptor With DNA. Nature. 1991;352:497–505. doi: 10.1038/352497a0. [DOI] [PubMed] [Google Scholar]
- Luther C., Adamopoulou E., Stoeckle C., Brucklacher-Waldert V., Rosenkranz D., Stoltze L., Lauer S., Poeschel S., Melms A., Tolosa E. Prednisolone treatment induces tolerogenic dendritic cells and a regulatory milieu in myasthenia gravis patients. J. Immunol. 2009;183:841–848. doi: 10.4049/jimmunol.0802046. [DOI] [PubMed] [Google Scholar]
- Madauss K.P., Bledsoe R.K., McLay I., Stewart E.L., Uings I.J., Weingarten G., Williams S.P. The first X-ray crystal structure of the glucocorticoid receptor bound to a non-steroidal agonist. Bioorg. Med. Chem. Lett. 2008;18:6097–6099. doi: 10.1016/j.bmcl.2008.10.021. [DOI] [PubMed] [Google Scholar]
- Maderna P., Yona S., Perretti M., Godson C. Modulation of phagocytosis of apoptotic neutrophils by supernatant from dexamethasone-treated macrophages and annexin-derived peptide Ac(2-26) J. Immunol. 2005;174:3727–3733. doi: 10.4049/jimmunol.174.6.3727. [DOI] [PubMed] [Google Scholar]
- Maier J.V., Brema S., Tuckermann J., Herzer U., Klein M., Stassen M., Moorthy A., Cato A.C. Dual specificity phosphatase 1 knockout mice show enhanced susceptibility to anaphylaxis but are sensitive to glucocorticoids. Mol. Endocrinol. 2007;21:2663–2671. doi: 10.1210/me.2007-0067. [DOI] [PubMed] [Google Scholar]
- Martinez F.O., Gordon S., Locati M., Mantovani A. Transcriptional profiling of the human monocyte-to-macrophage differentiation and polarization: new molecules and patterns of gene expression. J. Immunol. 2006;177:7303–7311. doi: 10.4049/jimmunol.177.10.7303. [DOI] [PubMed] [Google Scholar]
- McColl A., Bournazos S., Franz S., Perretti M., Morgan B.P., Haslett C., Dransfield I. Glucocorticoids induce protein S-dependent phagocytosis of apoptotic neutrophils by human macrophages. J. Immunol. 2009;183:2167–2175. doi: 10.4049/jimmunol.0803503. [DOI] [PubMed] [Google Scholar]
- McColl A., Michlewska S., Dransfield I., Rossi A.G. Effects of glucocorticoids on apoptosis and clearance of apoptotic cells. Sci. W. J. 2007;7:1165–1181. doi: 10.1100/tsw.2007.224. [DOI] [PMC free article] [PubMed] [Google Scholar]
- McEwen B.S., Biron C.A., Brunson K.W., Bulloch K., Chambers W.H., Dhabhar F.S., Goldfarb R.H., Kitson R.P., Miller A.H., Spencer R.L., Weiss J.M. The role of adrenocorticoids as modulators of immune function in health and disease: neural, endocrine and immune interactions. Brain Res. Rev. 1997;23:79–133. doi: 10.1016/s0165-0173(96)00012-4. [DOI] [PubMed] [Google Scholar]
- McKay L.I., Cidlowski J.A. Molecular control of immune/inflammatory responses: Interactions between NF-κB and steroid receptor-signaling pathways. Endocrinol. Rev. 1999;20:435–459. doi: 10.1210/edrv.20.4.0375. [DOI] [PubMed] [Google Scholar]
- McKnight S.L. McBindall—a better name for CCAAT/enhancer binding proteins? Cell. 2001;107:259–261. doi: 10.1016/s0092-8674(01)00543-8. [DOI] [PubMed] [Google Scholar]
- Meijsing S.H., Pufall M.A., So A.Y., Bates D.L., Chen L., Yamamoto K.R. DNA binding site sequence directs glucocorticoid receptor structure and activity. Science. 2009;324:407–410. doi: 10.1126/science.1164265. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Miesfeld R., Rusconi S., Godowski P.J., Maler B.A., Okret S., Wikström A.C., Gustafsson J.-Å., Yamamoto K.R. Genetic complementation of a glucocorticoid receptor deficiency by expression of cloned receptor cDNA. Cell. 1986;46:389–399. doi: 10.1016/0092-8674(86)90659-8. [DOI] [PubMed] [Google Scholar]
- Miller A.H., Spencer R.L., Stein M., McEwen B.S. Adrenal steroid receptor binding in spleen and thymus after stress or dexamethasone. Am. J. Physiol. 1990;259:E405–E412. doi: 10.1152/ajpendo.1990.259.3.E405. [DOI] [PubMed] [Google Scholar]
- Millward C.A., Heaney J.D., Sinasac D.S., Chu E.C., Bederman I.R., Gilge D.A., Previs S.F., Croniger C.M. Mice with a deletion in the gene for CCAAT/enhancer-binding protein β are protected against diet-induced obesity. Diabetes. 2007;56:161–167. doi: 10.2337/db06-0310. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Mozo L., Suarez A., Gutierrez C. Glucocorticoids up-regulate constitutive interleukin-10 production by human monocytes. Clin. Exp. Allergy. 2004;34:406–412. doi: 10.1111/j.1365-2222.2004.01824.x. [DOI] [PubMed] [Google Scholar]
- Munck A., Guyre P.M., Holbrook N.J. Physiological functions of glucocorticoids in stress and their relationship to pharmacological actions. Endocrinol. Rev. 1984;5:25–44. doi: 10.1210/edrv-5-1-25. [DOI] [PubMed] [Google Scholar]
- Muzikar K.A., Nickols N.G., Dervan P.B. Repression of DNA-binding dependent glucocorticoid receptor-mediated gene expression. Proc. Natl. Acad. Sci. U.S.A. 2009;106:16598–16603. doi: 10.1073/pnas.0909192106. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Necela B.M., Cidlowski J.A. Mechanisms of glucocorticoid receptor action in noninflammatory and inflammatory cells. Proc. Am. Thorac. Soc. 2004;1:239–246. doi: 10.1513/pats.200402-005MS. [DOI] [PubMed] [Google Scholar]
- Nerlov C. The C/EBP family of transcription factors: a paradigm for interaction between gene expression and proliferation control. Trends Cell Biol. 2007;17:318–324. doi: 10.1016/j.tcb.2007.07.004. [DOI] [PubMed] [Google Scholar]
- Newton R., Holden N.S. Separating transrepression and transactivation: a distressing divorce for the glucocorticoid receptor? Mol. Pharmacol. 2007;72:799–809. doi: 10.1124/mol.107.038794. [DOI] [PubMed] [Google Scholar]
- O'Sullivan B.J., Thomas R. CD40 Ligation conditions dendritic cell antigen-presenting function through sustained activation of NF-κB. J. Immunol. 2002;168:5491–5498. doi: 10.4049/jimmunol.168.11.5491. [DOI] [PubMed] [Google Scholar]
- Olsen N., Sokka T., Seehorn C.L., Kraft B., Maas K., Moore J., Aune T.M. A gene expression signature for recent onset rheumatoid arthritis in peripheral blood mononuclear cells. Ann. Rheum. Dis. 2004;63:1387–1392. doi: 10.1136/ard.2003.017194. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Payne V.A., Au W.S., Gray S.L., Nora E.D., Rahman S.M., Sanders R., Hadaschik D., Friedman J.E., O’Rahilly S., Rochford J.J. Sequential regulation of diacylglycerol acyltransferase 2 expression by CAAT/enhancer-binding protein beta (C/EBPβ) and C/EBPα during adipogenesis. J. Biol. Chem. 2007;282:21005–21014. doi: 10.1074/jbc.M702871200. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Payvar F., Defranco D., Firestone G.L., Edgar B., Wrange O., Okret S., Gustafsson J.A., Yamamoto K.R. Sequence-specific binding of glucocorticoid receptor to MTV DNA at sites within and upstream of the transcribed region. Cell. 1983;35:381–392. doi: 10.1016/0092-8674(83)90171-x. [DOI] [PubMed] [Google Scholar]
- Pazirandeh A., Jondal M., Okret S. Conditional expression of a glucocorticoid receptor transgene in thymocytes reveals a role for thymic-derived glucocorticoids in thymopoiesis in vivo. Endocrinology. 2005;146:2501–2507. doi: 10.1210/en.2004-0943. [DOI] [PubMed] [Google Scholar]
- Pazirandeh A., Xue Y., Prestegaard T., Jondal M., Okret S. Effects of altered glucocorticoid sensitivity in the T-cell lineage on thymocyte and T-cell homeostasis. FASEB J. 2002;16:727–729. doi: 10.1096/fj.01-0891fje. [DOI] [PubMed] [Google Scholar]
- Pearce D., Yamamoto K.R. Mineralocorticoid and glucocorticoid receptor activities distinguished by nonreceptor factors at a composite response element. Science. 1993;259:1161–1165. doi: 10.1126/science.8382376. [DOI] [PubMed] [Google Scholar]
- Penner G., Gang G., Sun X., Wray C., Hasselgren P.O. C/EBP DNA-binding activity is upregulated by a glucocorticoid-dependent mechanism in septic muscle. Am. J. Physiol. Regul. Integr. Comp. Physiol. 2002;282:R439–444. doi: 10.1152/ajpregu.00512.2001. [DOI] [PubMed] [Google Scholar]
- Pepin M.-C., Pothier F., Barden N. Impaired type II glucocorticoid receptor function in mice bearing antisense RNA transgene. Nature. 1992;355:725–728. doi: 10.1038/355725a0. [DOI] [PubMed] [Google Scholar]
- Perretti M., Ahluwalia A. The microcirculation and inflammation: site of action for glucocorticoids. Microcirculation. 2000;7:147–161. [PubMed] [Google Scholar]
- Perretti M., D’Acquisto F. Annexin A1 and glucocorticoids as effectors of the resolution of inflammation. Nat. Rev. Immunol. 2009;9:62–70. doi: 10.1038/nri2470. [DOI] [PubMed] [Google Scholar]
- Planey S.L., Litwack G. Glucocorticoid-induced apoptosis in lymphocytes. Biochem. Biophys. Res. Commun. 2000;279:307–312. doi: 10.1006/bbrc.2000.3922. [DOI] [PubMed] [Google Scholar]
- Purton J.F., Boyd R.L., Cole T.J., Godfrey D.I. Intrathymic T cell development and selection proceeds normally in the absence of glucocorticoid receptor signaling. Immunity. 2000;13:179–186. doi: 10.1016/s1074-7613(00)00018-2. [DOI] [PubMed] [Google Scholar]
- Purton J.F., Monk J.A., Liddicoat D.R., Kyparissoudis K., Sakkal S., Richardson S.J., Godfrey D.I., Cole T.J. Expression of the glucocorticoid receptor from the 1A promoter correlates with T lymphocyte sensitivity to glucocorticoid-induced cell death. J. Immunol. 2004;173:3816–3824. doi: 10.4049/jimmunol.173.6.3816. [DOI] [PubMed] [Google Scholar]
- Purton J.F., Zhan Y., Liddicoat D.R., Hardy C.L., Lew A.M., Cole T.J., Godfrey D.I. Glucocorticoid receptor deficient thymic and peripheral T cells develop normally in adult mice. Eur. J. Immunol. 2002;32:3546–3555. doi: 10.1002/1521-4141(200212)32:12<3546::AID-IMMU3546>3.0.CO;2-S. [DOI] [PubMed] [Google Scholar]
- Rea D., van Kooten C., van Meijgaarden K.E., Ottenhoff T.H., Melief C.J., Offringa R. Glucocorticoids transform CD40-triggering of dendritic cells into an alternative activation pathway resulting in antigen-presenting cells that secrete IL-10. Blood. 2000;95:3162–3167. [PubMed] [Google Scholar]
- Reddy T.E., Pauli F., Sprouse R.O., Neff N.F., Newberry K.M., Garabedian M.J., Myers R.M. Genomic determination of the glucocorticoid response reveals unexpected mechanisms of gene regulation. Genome Res. 2009;19:2163–2171. doi: 10.1101/gr.097022.109. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Reichardt H.M., Kaestner K.H., Tuckermann J., Kretz O., Wessely O., Bock R., Gass P., Schmid W., Herrlich P., Angel P., Schütz G. DNA binding of the glucocorticoid receptor is not essential for survival. Cell. 1998;93:531–541. doi: 10.1016/s0092-8674(00)81183-6. [DOI] [PubMed] [Google Scholar]
- Reichardt H.M., Tuckermann J.P., Gottlicher M., Vujic M., Weih F., Angel P., Herrlich P., Schutz G. Repression of inflammatory responses in the absence of DNA binding by the glucocorticoid receptor. EMBO J. 2001;20:7168–7173. doi: 10.1093/emboj/20.24.7168. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Reichardt H.M., Umland T., Bauer A., Kretz O., Schütz G. Mice with an increased glucocorticoid receptor gene dosage show enhanced resistance to stress and endotoxic shock. Mol. Cell. Biol. 2000;20:9009–9017. doi: 10.1128/mcb.20.23.9009-9017.2000. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Rennick D., Davidson N., Berg D. Interleukin-10 gene knock-out mice: a model of chronic inflammation. Clin. Immunol. Immunopathol. 1995;76:S174–S178. doi: 10.1016/s0090-1229(95)90144-2. [DOI] [PubMed] [Google Scholar]
- Rhen T., Cidlowski J.A. Antiinflammatory action of glucocorticoids - new mechanisms for old drugs. N. Engl. J. Med. 2005;353:1711–1723. doi: 10.1056/NEJMra050541. [DOI] [PubMed] [Google Scholar]
- Richards D.F., Fernandez M., Caulfield J., Hawrylowicz C.M. Glucocorticoids drive human CD8(+) T cell differentiation towards a phenotype with high IL-10 and reduced IL-4 IL-5 and IL-13 production. Eur. J. Immunol. 2000;30:2344–2354. doi: 10.1002/1521-4141(2000)30:8<2344::AID-IMMU2344>3.0.CO;2-7. [DOI] [PubMed] [Google Scholar]
- Rogatsky I., Wang J.C., Derynck M.K., Nonaka D.F., Khodabakhsh D.B., Haqq C.M., Darimont B.D., Garabedian M.J., Yamamoto K.R. Target-specific utilization of transcriptional regulatory surfaces by the glucocorticoid receptor. Proc. Natl. Acad. Sci. U.S.A. 2003;100:13845–13850. doi: 10.1073/pnas.2336092100. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Rook G.A., Hernandez-Pando R., Lightman S.L. Hormones, peripherally activated prohormones and regulation of the Th1/Th2 balance. Immunol. Today. 1994;15:301–303. doi: 10.1016/0167-5699(94)90075-2. [DOI] [PubMed] [Google Scholar]
- Rosenstock J., Banarer S., Fonseca V., Inzucchi S., Holllis G., Flores R., Levy R., Williams B., Huber R. Efficacy and safety of the 11β-HSD1 inhibitor, INCB13739, added to metformin therapy in patients with type 2 diabetes; Abstracts of the 69th Meeting of the American Diabetes Association, New Orleans; 2009. 7-LB. [Google Scholar]
- Ruffell D., Mourkioti F., Gambardella A., Kirstetter P., Lopez R.G., Rosenthal N., Nerlov C. A CREB-C/EBPβ cascade induces M2 macrophage-specific gene expression and promotes muscle injury repair. Proc. Natl. Acad. Sci. U.S.A. 2009;106:17475–17480. doi: 10.1073/pnas.0908641106. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Rutella S., Lemoli R.M. Regulatory T cells and tolerogenic dendritic cells: from basic biology to clinical applications. Immunol. Lett. 2004;94:11–26. doi: 10.1016/j.imlet.2004.04.015. [DOI] [PubMed] [Google Scholar]
- Sai S., Esteves C.L., Kelly V., Michailidou Z., Anderson K., Coll A.P., Nakagawa Y., Ohzeki T., Seckl J.R., Chapman K.E. Glucocorticoid regulation of the promoter of 11β-hydroxysteroid dehydrogenase type 1 is indirect and requires C/EBPβ. Mol. Endocrinol. 2008;22:2049–2060. doi: 10.1210/me.2007-0489. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Sai S., Nakagawa Y., Sakaguchi K., Okada S., Takahashi H., Hongo T., Seckl J.R., Chapman K.E., Ohzeki T. Differential regulation of 11β-hydroxysteroid dehydrogenase-1 by dexamethasone in glucocorticoid-sensitive and -resistant childhood lymphoblastic leukemia. Leuk. Res. 2009;33:1696–1698. doi: 10.1016/j.leukres.2009.04.016. [DOI] [PubMed] [Google Scholar]
- Salojin K.V., Owusu I.B., Millerchip K.A., Potter M., Platt K.A., Oravecz T. Essential role of MAPK phosphatase-1 in the negative control of innate immune responses. J. Immunol. 2006;176:1899–1907. doi: 10.4049/jimmunol.176.3.1899. [DOI] [PubMed] [Google Scholar]
- Savill J., Dransfield I., Gregory C., Haslett C. A blast from the past: clearance of apoptotic cells regulates immune responses. Nat. Rev. Immunol. 2002;2:965–975. doi: 10.1038/nri957. [DOI] [PubMed] [Google Scholar]
- Savoldi G., Fenaroli A., Ferrari F., Rigaud G., Albertini A., Di Lorenzo D. The glucocorticoid receptor regulates the binding of C/EBPβ on the α1-acid glycoprotein promoter in vivo. DNA Cell Biol. 1997;16:1467–1476. doi: 10.1089/dna.1997.16.1467. [DOI] [PubMed] [Google Scholar]
- Schacke H., Berger M., Rehwinkel H., Asadullah K. Selective glucocorticoid receptor agonists (SEGRAs): novel ligands with an improved therapeutic index. Mol. Cell. Endocrinol. 2007;275:109–117. doi: 10.1016/j.mce.2007.05.014. [DOI] [PubMed] [Google Scholar]
- Scheinman R.I., Cogswell P.C., Lofquist A.K., Baldwin A.S. Role of transcriptional activation of IκBα in mediation of immunosuppression by glucocorticoids. Science. 1995;270:283–286. doi: 10.1126/science.270.5234.283. [DOI] [PubMed] [Google Scholar]
- Schmidt M., Weidler C., Naumann H., Anders S., Scholmerich J., Straub R.H. Reduced capacity for the reactivation of glucocorticoids in rheumatoid arthritis synovial cells: Possible role of the sympathetic nervous system? Arthritis Rheum. 2005;52:1711–1720. doi: 10.1002/art.21091. [DOI] [PubMed] [Google Scholar]
- Schroeder-Gloeckler J.M., Rahman S.M., Janssen R.C., Qiao L., Shao J., Roper M., Fischer S.J., Lowe E., Orlicky D.J., McManaman J.L., Palmer C., Gitomer W.L., Huang W., O’Doherty R.M., Becker T.C., Klemm D.J., Jensen D.R., Pulawa L.K., Eckel R.H., Friedman J.E. CCAAT/enhancer-binding protein-β deletion reduces adiposity, hepatic steatosis, and diabetes in Lepr(db/db) mice. J. Biol. Chem. 2007;282:15717–15729. doi: 10.1074/jbc.M701329200. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Seckl J.R. 11β-hydroxysteroid dehydrogenases. Encyclopedia Stress. 2000;2:413–421. [Google Scholar]
- Seckl J.R., Morton N.M., Chapman K.E., Walker B.R. Glucocorticoids and 11β-hydroxysteroid dehydrogenase in adipose tissue. Recent Prog. Horm. Res. 2004;59:359–393. doi: 10.1210/rp.59.1.359. [DOI] [PubMed] [Google Scholar]
- Serhan C.N., Savill J. Resolution of inflammation: the beginning programs the end. Nat. Immunol. 2005;6:1191–1197. doi: 10.1038/ni1276. [DOI] [PubMed] [Google Scholar]
- Shanks N., Windle R.J., Perks P.A., Harbuz M.S., Jessop D.S., Ingram C.D., Lightman S.L. Early-life exposure to endotoxin alters hypothalamic-pituitary-adrenal function and predisposition to inflammation. Proc. Natl. Acad. Sci. U.S.A. 2000;97:5645–5650. doi: 10.1073/pnas.090571897. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Sica A., Bronte V. Altered macrophage differentiation and immune dysfunction in tumor development. J. Clin. Invest. 2007;117:1155–1166. doi: 10.1172/JCI31422. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Simons S.S., Jr What goes on behind closed doors: physiological versus pharmacological steroid hormone actions. Bioessays. 2008;30:744–756. doi: 10.1002/bies.20792. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Smoak K.A., Cidlowski J.A. Mechanisms of glucocorticoid receptor signaling during inflammation. Mech. Ageing Dev. 2004;125:697–706. doi: 10.1016/j.mad.2004.06.010. [DOI] [PubMed] [Google Scholar]
- So A.Y., Chaivorapol C., Bolton E.C., Li H., Yamamoto K.R. Determinants of cell- and gene-specific transcriptional regulation by the glucocorticoid receptor. PLoS Genet. 2007;3:e94. doi: 10.1371/journal.pgen.0030094. [DOI] [PMC free article] [PubMed] [Google Scholar]
- So A.Y., Cooper S.B., Feldman B.J., Manuchehri M., Yamamoto K.R. Conservation analysis predicts in vivo occupancy of glucocorticoid receptor-binding sequences at glucocorticoid-induced genes. Proc. Natl. Acad. Sci. U.S.A. 2008;105:5745–5749. doi: 10.1073/pnas.0801551105. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Solito E., Mulla A., Morris J.F., Christian H.C., Flower R.J., Buckingham J.C. Dexamethasone induces rapid serine-phosphorylation and membrane translocation of annexin 1 in a human folliculostellate cell line via a novel nongenomic mechanism involving the glucocorticoid receptor, protein kinase C, phosphatidylinositol 3-kinase, and mitogen-activated protein kinase. Endocrinology. 2003;144:1164–1174. doi: 10.1210/en.2002-220592. [DOI] [PubMed] [Google Scholar]
- Sorrells S.F., Caso J.R., Munhoz C.D., Sapolsky R.M. The stressed CNS: when glucocorticoids aggravate inflammation. Neuron. 2009;64:33–39. doi: 10.1016/j.neuron.2009.09.032. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Souverein P.C., Berard A., Van Staa T.P., Cooper C., Egberts A.C.G., Leufkens H.G.M., Walker B.R. Use of oral glucocorticoids and risk of cardiovascular and cerebrovascular disease in a population based case-control study. Heart. 2004;90:859–865. doi: 10.1136/hrt.2003.020180. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Staiger J., Lueben M.J., Berrigan D., Malik R., Perkins S.N., Hursting S.D., Johnson P.F. C/EBPβ regulates body composition, energy balance-related hormones, and tumor growth. Carcinogenesis. 2008;30:832–840. doi: 10.1093/carcin/bgn273. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Stavreva D.A., Wiench M., John S., Conway-Campbell B.L., McKenna M.A., Pooley J.R., Johnson T.A., Voss T.C., Lightman S.L., Hager G.L. Ultradian hormone stimulation induces glucocorticoid receptor-mediated pulses of gene transcription. Nat. Cell Biol. 2009;11:1093–1102. doi: 10.1038/ncb1922. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Stellato C. Post-transcriptional and nongenomic effects of glucocorticoids. Proc. Am. Thorac. Soc. 2004;1:255–263. doi: 10.1513/pats.200402-015MS. [DOI] [PubMed] [Google Scholar]
- Sternberg E.M. Neural regulation of innate immunity: a coordinated nonspecific host response to pathogens. Nat. Rev. Immunol. 2006;6:318–328. doi: 10.1038/nri1810. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Tchen C.R., Martins J.R., Paktiawal N., Perelli R., Saklatvala J., Clark A.R. Glucocorticoid regulation of mouse and human dual specificity phosphatase 1 (DUSP1) genes: unusual cis-acting elements and unexpected evolutionary divergence. J. Biol. Chem. 2009;(November (23)) doi: 10.1074/jbc.M109.037309. Epub ahead of print. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Thieringer R., Le Grand C.B., Carbin L., Cai T.Q., Wong B., Wright S.D., Hermanowski-Vosatka A. 11β-Hydroxysteroid dehydrogenase type 1 is induced in human monocytes upon differentiation to macrophages. J. Immunol. 2001;167:30–35. doi: 10.4049/jimmunol.167.1.30. [DOI] [PubMed] [Google Scholar]
- Tuckermann J.P., Kleiman A., McPherson K.G., Reichardt H.M. Molecular mechanisms of glucocorticoids in the control of inflammation and lymphocyte apoptosis. Crit. Rev. Clin. Lab Sci. 2005;42:71–104. doi: 10.1080/10408360590888983. [DOI] [PubMed] [Google Scholar]
- Tuckermann J.P., Kleiman A., Moriggl R., Spanbroek R., Neumann A., Illing A., Clausen B.E., Stride B., Forster I., Habenicht A.J., Reichardt H.M., Tronche F., Schmid W., Schutz G. Macrophages and neutrophils are the targets for immune suppression by glucocorticoids in contact allergy. J. Clin. Invest. 2007;117:1381–1390. doi: 10.1172/JCI28034. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Umesono K., Evans R.M. Determinants of target gene specificity for steroid/thyroid hormone receptors. Cell. 1989;57:1139–1146. doi: 10.1016/0092-8674(89)90051-2. [DOI] [PubMed] [Google Scholar]
- van der Laan S., Sarabdjitsingh R.A., Van Batenburg M.F., Lachize S.B., Li H., Dijkmans T.F., Vreugdenhil E., de Kloet E.R., Meijer O.C. Chromatin immunoprecipitation scanning identifies glucocorticoid receptor binding regions in the proximal promoter of a ubiquitously expressed glucocorticoid target gene in brain. J. Neurochem. 2008;106:2515–2523. doi: 10.1111/j.1471-4159.2008.05575.x. [DOI] [PubMed] [Google Scholar]
- van Staa T.P., Leufkens H.G.M., Abenhaim L., Begaud B., Zhang B., Cooper C. Use of oral corticosteroids in the United Kingdom. QJM. 2000;93:105–111. doi: 10.1093/qjmed/93.2.105. [DOI] [PubMed] [Google Scholar]
- van Tilborg M.A., Lefstin J.A., Kruiskamp M., Teuben J., Boelens R., Yamamoto K.R., Kaptein R. Mutations in the glucocorticoid receptor DNA-binding domain mimic an allosteric effect of DNA. J. Mol. Biol. 2000;301:947–958. doi: 10.1006/jmbi.2000.4001. [DOI] [PubMed] [Google Scholar]
- Varga G., Ehrchen J., Tsianakas A., Tenbrock K., Rattenholl A., Seeliger S., Mack M., Roth J., Sunderkoetter C. Glucocorticoids induce an activated, anti-inflammatory monocyte subset in mice that resembles myeloid-derived suppressor cells. J. Leukoc. Biol. 2008;84:644–650. doi: 10.1189/jlb.1107768. [DOI] [PubMed] [Google Scholar]
- Vegiopoulos A., Herzig S. Glucocorticoids, metabolism and metabolic diseases. Mol. Cell Endocrinol. 2007;275:43–61. doi: 10.1016/j.mce.2007.05.015. [DOI] [PubMed] [Google Scholar]
- Wang D., Muller N., McPherson K.G., Reichardt H.M. Glucocorticoids engage different signal transduction pathways to induce apoptosis in thymocytes and mature T cells. J. Immunol. 2006;176:1695–1702. doi: 10.4049/jimmunol.176.3.1695. [DOI] [PubMed] [Google Scholar]
- Wang J.C., Derynck M.K., Nonaka D.F., Khodabakhsh D.B., Haqq C., Yamamoto K.R. Chromatin immunoprecipitation (ChIP) scanning identifies primary glucocorticoid receptor target genes. Proc. Natl. Acad. Sci. U.S.A. 2004;101:15603–15608. doi: 10.1073/pnas.0407008101. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Webster J.I., Tonelli L., Sternberg E.M. Neuroendocrine regulation of immunity. Annu. Rev. Immunol. 2002;20:125–163. doi: 10.1146/annurev.immunol.20.082401.104914. [DOI] [PubMed] [Google Scholar]
- Wei L., MacDonald T.M., Walker B.R. Taking glucocorticoids by prescription is associated with subsequent cardiovascular disease. Ann. Intern. Med. 2004;141:764–770. doi: 10.7326/0003-4819-141-10-200411160-00007. [DOI] [PubMed] [Google Scholar]
- White P.C., Rogoff D., McMillan D.R., Lavery G.G. Hexose 6-phosphate dehydrogenase (H6PD) and corticosteroid metabolism. Mol. Cell. Endocrinol. 2007;265-266:89–92. doi: 10.1016/j.mce.2006.12.022. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Whorwood C.B., Franklyn J.A., Sheppard M.C., Stewart P.M. Tissue localisation of 11β-hydroxysteroid dehydrogenase and its relationship to the glucocorticoid receptor. J. Steroid Biochem. Mol. Biol. 1992;41:21–28. doi: 10.1016/0960-0760(92)90220-d. [DOI] [PubMed] [Google Scholar]
- Whyte M.K., Meagher L.C., MacDermot J., Haslett C. Impairment of function in aging neutrophils is associated with apoptosis. J. Immunol. 1993;150:5124–5134. [PubMed] [Google Scholar]
- Wilckens T. Glucocorticoids and immune function: physiological relevance and pathogenic potential of hormonal dysfunction. Trends Pharmacol. Sci. 1995;16:193–197. doi: 10.1016/s0165-6147(00)89021-5. [DOI] [PubMed] [Google Scholar]
- Wilckens T., De Rijk R. Glucocorticoids and immune function: unknown dimensions and new frontiers. Immunol. Today. 1997;18:418–424. doi: 10.1016/s0167-5699(97)01111-0. [DOI] [PubMed] [Google Scholar]
- Williams L.J.S., Lyons V., MacLeod I., Rajan V., Darlington G.J., Poli V., Seckl J.R., Chapman K.E. C/EBP regulates hepatic transcription of 11β-hydroxysteroid dehydrogenase type 1; a novel mechanism for cross talk between the C/EBP and glucocorticoid signalling pathways. J. Biol. Chem. 2000;275:30232–30239. doi: 10.1074/jbc.M001286200. [DOI] [PubMed] [Google Scholar]
- Wissink S., van Heerde E.C., vand der Burg B., van der Saag P.T. A dual mechanism mediates repression of NF-κB activity by glucocorticoids. Mol. Endocrinol. 1998;12:355–363. doi: 10.1210/mend.12.3.0081. [DOI] [PubMed] [Google Scholar]
- Wu J.J., Roth R.J., Anderson E.J., Hong E.-G., Lee M.-K., Choi C.S., Neufer P.D., Shulman G.I., Kim J.K., Bennett A.M. Mice lacking MAP kinase phosphatase-1 have enhanced MAP kinase activity and resistance to diet-induced obesity. Cell Metab. 2006;4:61–73. doi: 10.1016/j.cmet.2006.05.010. [DOI] [PubMed] [Google Scholar]
- Wust S., van den Brandt J., Tischner D., Kleiman A., Tuckermann J.P., Gold R., Luhder F., Reichardt H.M. Peripheral T cells are the therapeutic targets of glucocorticoids in experimental autoimmune encephalomyelitis. J. Immunol. 2008;180:8434–8443. doi: 10.4049/jimmunol.180.12.8434. [DOI] [PubMed] [Google Scholar]
- Yamada K., Duong D.T., Scott D.K., Wang J.-C., Granner D.K. CCAAT/enhancer-binding protein β is an accessory factor for the glucocorticoid response from the cAMP response element in the rat phosphoenolpyruvate carboxykinase gene promoter. J. Biol. Chem. 1999;274:5880–5887. doi: 10.1074/jbc.274.9.5880. [DOI] [PubMed] [Google Scholar]
- Yamamoto K.R. Steroid receptor regulated transcription of specific genes and gene networks. Ann. Rev. Genet. 1985;19:209–252. doi: 10.1146/annurev.ge.19.120185.001233. [DOI] [PubMed] [Google Scholar]
- Yang H., Mammen J., Wei W., Menconi M., Evenson A., Fareed M., Petkova V., Hasselgren P.O. Expression and activity of C/EBPβ and δ are upregulated by dexamethasone in skeletal muscle. J. Cell. Physiol. 2005;204:219–226. doi: 10.1002/jcp.20278. [DOI] [PubMed] [Google Scholar]
- Yang H., Menconi M.J., Wei W., Petkova V., Hasselgren P.O. Dexamethasone upregulates the expression of the nuclear cofactor p300 and its interaction with C/EBPβ in cultured myotubes. J. Cell. Biochem. 2005;94:1058–1067. doi: 10.1002/jcb.20371. [DOI] [PubMed] [Google Scholar]
- Yang Y.H., Aeberli D., Dacumos A., Xue J.R., Morand E.F. Annexin-1 regulates macrophage IL-6 and TNF via glucocorticoid-induced leucine zipper. J. Immunol. 2009;183:1435–1445. doi: 10.4049/jimmunol.0804000. [DOI] [PubMed] [Google Scholar]
- Yang Y.H., Morand E.F., Getting S.J., Paul-Clark M., Liu D.L., Yona S., Hannon R., Buckingham J.C., Perretti M., Flower R.J. Modulation of inflammation and response to dexamethasone by Annexin 1 in antigen-induced arthritis. Arthritis Rheum. 2004;50:976–984. doi: 10.1002/art.20201. [DOI] [PubMed] [Google Scholar]
- Yang Z., Guo C., Zhu P., Li W., Myatt L., Sun K. Role of glucocorticoid receptor and CCAAT/enhancer-binding protein-α in the feed-forward induction of 11β-hydroxysteroid dehydrogenase type 1 expression by cortisol in human amnion fibroblasts. J. Endocrinol. 2007;195:241–253. doi: 10.1677/JOE-07-0303. [DOI] [PubMed] [Google Scholar]
- Yang Z., Zhu X., Guo C., Sun K. Stimulation of 11β-HSD1 expression by IL-1β via a C/EBP binding site in human fetal lung fibroblasts. Endocrine. 2009;36:404–411. doi: 10.1007/s12020-009-9245-4. [DOI] [PubMed] [Google Scholar]
- Yangyen H.F., Chambard J.C., Sun Y.L., Smeal T., Schmidt T.J., Drouin J., Karin M. Transcriptional interference between c-Jun and the glucocorticoid receptor: mutual inhibition of DNA binding due to direct protein-protein interaction. Cell. 1990;62:1205–1215. doi: 10.1016/0092-8674(90)90396-v. [DOI] [PubMed] [Google Scholar]
- Yeager M.P., Guyre P.M., Munck A.U. Glucocorticoid regulation of the inflammatory response to injury. Acta Anaesthesiol. Scand. 2004;48:799–813. doi: 10.1111/j.1399-6576.2004.00434.x. [DOI] [PubMed] [Google Scholar]
- Yona S., Buckingham J.C., Perretti M., Flower R.J. Stimulus-specific defect in the phagocytic pathways of annexin 1 null macrophages. Br. J. Pharmacol. 2004;142:890–898. doi: 10.1038/sj.bjp.0705858. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Yoshinaga S.K., Yamamoto K.R. Signaling and regulation by a mammalian glucocorticoid receptor in Drosophila cells. Mol. Endocrinol. 1991;5:844–853. doi: 10.1210/mend-5-6-844. [DOI] [PubMed] [Google Scholar]
- Zbankova S., Bryndova J., Leden P., Kment M., Svec A., Pacha J. 11β-hydroxysteroid dehydrogenase 1 and 2 expression in colon from patients with ulcerative colitis. J. Gastroenterol. Hepatol. 2007;22:1019–1023. doi: 10.1111/j.1440-1746.2006.04529.x. [DOI] [PubMed] [Google Scholar]
- Zhang J., Ge R., Matte-Martone C., Goodwin J., Shlomchik W.D., Mamula M.J., Kooshkabadi A., Hardy M.P., Geller D. Characterization of a novel gain of function glucocorticoid receptor knock-in mouse. J. Biol. Chem. 2009;284:6249–6259. doi: 10.1074/jbc.M807997200. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Zhang T.Y., Daynes R.A. Macrophages from 11β-hydroxysteroid dehydrogenase type 1-deficient mice exhibit an increased sensitivity to lipopolysaccharide stimulation due to TGF-β-mediated up-regulation of SHIP1 expression. J. Immunol. 2007;179:6325–6335. doi: 10.4049/jimmunol.179.9.6325. [DOI] [PubMed] [Google Scholar]
- Zhang T.Y., Ding X., Daynes R.A. The expression of 11β-hydroxysteroid dehydrogenase type I by lymphocytes provides a novel means for intracrine regulation of glucocorticoid activities. J. Immunol. 2005;174:879–889. doi: 10.4049/jimmunol.174.2.879. [DOI] [PubMed] [Google Scholar]
- Zhao Q., Wang X., Nelin L.D., Yao Y., Matta R., Manson M.E., Baliga R.S., Meng X., Smith C.V., Bauer J.A., Chang C.H., Liu Y. MAP kinase phosphatase 1 controls innate immune responses and suppresses endotoxic shock. J. Exp. Med. 2006;203:131–140. doi: 10.1084/jem.20051794. [DOI] [PMC free article] [PubMed] [Google Scholar]