gp130 at the nexus of inflammation, autoimmunity, and cancer

Review highlights the function of the cytokine receptor gp130, specifically the diverse roles it plays in inflammation, autoimmunity, and cancer.

Abstract

Glycoprotein 130 (gp130) is a shared receptor utilized by several related cytokines, including IL-6, IL-11, IL-27, Leukemia Inhibitory Factor (LIF), Oncostatin M (OSM), Ciliary Neurotrophic Factor (CNTF), Cardiotrophin 1 (CT-1) and Cardiotrophin-like Cytokine (CLC). Gp130 plays critical roles during development and gp130-deficient mice are embryonically lethal. However, the best characterized facet of this receptor and its associated cytokines is the ability to promote or suppress inflammation. The aim of this review is to discuss the role of gp130 in promoting or preventing the development of autoimmunity and cancer, two processes that are associated with aberrant inflammatory responses.

Introduction

gp130 is a ubiquitously expressed, signal-transducing receptor that forms part of the receptor complex for several cytokines, including IL-6, IL-11, IL-27, leukemia inhibitory factor, OSM, CNTF, cardiotrophin 1, and cardiotrophin-like cytokine [1]. gp130 was described initially in mice as a membrane-bound glycoprotein, absent on resting lymphocytes but present on blasting T cells. It is now recognized that gp130 is present on hematopoietic and nonhematopoietic cells, and its expression can vary, depending on the cell's activation status [1–5]. In mammals, gp130 is involved in a wide variety of critical processes, illustrated by the fact that gp130-deficient mice are embryonically lethal as a result of ventricular myocardial hypoplasia and defects in hematopoiesis [6]. Similarly, conditional deletion of gp130 after birth results in hematopoietic, cardiac, neurological, hepatic, pulmonary, and immunological defects [7, 8]. The evolutionary importance of this receptor is illustrated by the presence of a homologous receptor called dome in Drosophila melanogaster, which is involved in embryonic segmentation, eye development, and immunity [9–11]. Although gp130 has many functions, the aim of this review is to highlight the diverse mechanisms by which gp130 and its associated cytokines affect inflammation and how this influences the development of autoimmunity and cancer.

INITIATION OF gp130-MEDIATED SIGNALING

Since the initial description of gp130 in 1978, multiple studies have helped to define the mechanisms underlying gp130-mediated signaling, and it is now appreciated that gp130 can associate with a number of cytokine-specific α chains to mediate signal transduction [12, 13]. The interactions between gp130 and IL-6 have provided the template for understanding how other family members signal. Thus, when IL-6 binds to the IL-6Rα, it triggers a heterodimeric association with gp130 to form a signaling complex composed of a gp130 homodimer plus two IL-6Rα [14, 15]. IL-11 also forms a similar hexameric signaling complex, but it is thought that the other gp130 cytokines signal through a receptor complex containing a single gp130 chain and a cytokine-specific receptor α chain [1]. An extensive discussion of the structural basis for how different cytokines and receptor subunits interact and promote signaling is provided by Garcia and colleagues [16].

Engagement of gp130 with cytokine-specific α chains triggers the activation of three signaling cassettes, most prominently the JAK-STAT pathway (Fig. 1). Under normal circumstances, the Janus kinases JAK1, JAK2, and tyrosine kinase 2 are constitutively associated with gp130, but receptor engagement leads to their phosphorylation and activation [17, 18]. These enzymes then phosphorylate the STAT, which allows these molecules to translocate to the nucleus and initiate gene transcription. Typically, signaling through gp130 can activate STAT1, STAT3, and STAT5. Engagement of gp130 also leads to the recruitment of the cytoplasmic protein tyrosine phosphatase SHP2, which activates the Ras-ERK1/2 MAPK and PI3K/AKT pathways [19, 20]. Much of the work on gp130-mediated signaling focuses on its activation of the JAK-STAT pathway, which will be discussed in greater detail below, but less is known about the biological consequences of gp130-mediated MAPK or PI3K/AKT activity.

Figure 1. gp130-mediated signaling.

(A) gp130 family cytokines, in this case, IL-6, bind their specific receptor α chains, which triggers association with gp130 and formation of a multimeric complex. (B) Receptor-associated JAK molecules are phosphorylated and in turn, phosphorylate and activate recruited STAT molecules (pSTAT). gp130 signaling typically activates STAT1, -3, and/or -5. As a consequence of receptor engagement, SHP2 is recruited and can activate the PI3K or ERK/MAPK pathways downstream, although relatively little is understood about the biological significance of these pathways. (C) SOCS3 is up-regulated in response to STAT1 and STAT3 and can bind directly to gp130 and block signal transduction, thus acting in a negative-feedback loop.

The contribution of cytokine-specific α chains to signal transduction is variable. For example, the intracellular domain of the IL-6Rα and IL-11Rα lacks STAT-binding sites. In contrast, the IL-27Rα WSX-1 has a box 1 motif that is required for association with Janus kinases, and previous work suggests that WSX-1 is capable of signal transduction [21–23]. Regardless of the contribution of the cytokine-specific α chains, it is clear that gp130 is required for signal transduction for each of these cytokines. Further complexity in gp130 signaling mechanisms is illustrated by the presence of soluble receptors for CNTF and IL-6. The soluable CNTFR is not as well characterized, but it is clear that the sIL-6Rα can be generated through alternative splicing or enzymatic cleavage of the membrane-bound form [24–26]. The sIL-6Rα can pair with free IL-6, and this heterodimer can bind to gp130 and activate the downstream signaling cascades on cells that do not express the IL-6Rα. This process is referred to as trans-signaling. There are basal levels of circulating sIL-6R that are elevated during inflammation [27]. It is notable that the pairing of sIL-6Rα with IL-6 structurally resembles the heterodimeric cytokines IL-12, IL-23, and IL-27, and it has been proposed that these heterodimeric cytokines evolved from an ancestral IL-6/IL-6R-like complex [28]. Nevertheless, the ubiquitous expression of gp130, combined with the availability of IL-6 and the sIL-6Rα, suggests that virtually any cell is able to respond to IL-6. Thus, despite the multiplicity of cytokines that use gp130, IL-6 may influence the widest range of cell types as a result of its ability to use trans-signaling, and this might represent the dominant mechanism by which this cytokine influences inflammatory responses [29, 30].

Regulation of gp130-mediated signaling

As with many signaling cascades, there is a variety of feedback mechanisms that serves to limit and control cytokine-mediated JAK-STAT signaling, including the dissociation of receptor-associated JAK molecules, endocytosis of the receptor complex, and nuclear export of activated STAT molecules [31, 32]. However, the SOCS proteins are regarded as the primary negative regulators of gp130-mediated signaling and were characterized in a genetic screen to identify cells that were unresponsive to IL-6 [33, 34]. Among SOCS family members, SOCS3 acts in a negative-feedback loop to limit gp130-mediated signaling specifically by binding to a tyrosine residue at position 757 in mice and 759 in humans (Fig. 1) [33, 35, 36]. For a more detailed review of the SOCS family and its role in negatively regulating cytokine signaling, see Yoshimura et al. [37]. The significance of this negative regulatory mechanism is illustrated by mice that are engineered to express mutated forms of gp130 lacking the SOCS3-binding site; these mice develop a variety of hematopoietic and immunological defects, which will be discussed in greater detail in sections below [38, 39]. Moreover, STAT signaling, in response to gp130, is sustained in cells that lack SOCS3, highlighting the critical role of this protein in limiting gp130-mediated signaling [35, 40–42]. In WT cells, IL-6 signaling results in an abbreviated period of STAT3 activation, and IL-10 signaling yields a more sustained period of STAT3 activation (Fig. 2). However, in cells that lack SOCS3, the period of STAT3 activation after IL-6/gp130-mediated signaling is sustained, and IL-6 acquires anti-inflammatory properties normally associated with IL-10. Thus, SOCS3 controls the duration and quality of gp130-mediated signaling. It is important to note, however, that the signal is terminated eventually, suggesting that there are other mechanisms that can regulate gp130 signaling in the absence of SOCS3.

Figure 2. SOCS3 regulates the quality of gp130-mediated signaling.

(A) In WT cells, IL-6 signaling results in an abbreviated period of STAT3 activation. (B) This contrasts with IL-10 signaling, which also uses STAT3, but results in a more sustained period of STAT3 activation. (C) In gp130 Y757F or Y759F mice or in mice that genetically lack SOCS3, IL-6-mediated activation of STAT3 is more sustained. In this case, IL-6 acquires the ability to block proinflammatory cytokine production from activated macrophages. These studies demonstrate that SOCS3 regulates the nature of the cellular response to gp130-mediated signals. Although STAT signaling is sustained in the absence of SOCS3, other unclear mechanisms can compensate, and the signal terminates eventually.

THE ROLE OF gp130 DURING INFLAMMATION

The link between gp130 cytokines and the development of inflammation is perhaps the most well-characterized facet of this receptor. Inflammatory processes are characterized by the coordinated recruitment and retention of hematopoietic cells to sites of cellular injury. Proper control of these events is absolutely essential for the generation of protective immunity to pathogens and to limit the adverse consequences associated with chronic inflammation. Understanding the effects of gp130 during inflammation has been difficult as a result of the perinatal lethality associated with gp130 deficiency. This problem was circumvented with experimental approaches using mice that express floxed alleles of gp130. In one study, mice which expressed the Cre recombinase under control of the IFN-responsive Mx promoter could be treated with IFN-α to delete gp130 in hepatocytes and multiple lymphoid tissues after birth [7]. These mice, when given dextran sulfate sodium to induce colitis, have reduced expression of inflammatory cytokines, chemokines, and adhesion molecules in the mucosa [43]. Critically, the mice are protected from severe pathology and weight loss, as a result of significantly diminished recruitment of leukocytes to the inflamed mucosa. This study demonstrates the direct role that gp130 plays in regulating cellular recruitment to local sites of inflammation.

IL-6 as an ″immunological switch″

The successful initiation of acute inflammation is characterized by recruitment of neutrophils, followed by the sustained recruitment of mononuclear cells associated with chronic inflammation. This shift in cellular recruitment has been referred to as an immunological switch and is a critical step in the progression and resolution of inflammation [44]. There has long been an appreciation of the link between IL-6 and acute inflammation, and recent reports have provided insight into the complex biology underlying these effects by demonstrating key roles for IL-6 trans-signaling at multiple stages during the transition from acute to chronic inflammation [29]. For example, neutrophils infiltrating a site of inflammation can cleave the membrane IL-6Rα, thus generating the sIL-6Rα and allowing IL-6 to signal in-trans to resident tissue stromal cells. IL-6 trans-signaling has been shown to augment production of ICAM-1, CXCL5, CXCL6, CCL2, and CCL8 and block production of CXCL1, CXCL8, and CX3CL1 [29]. Additionally, in patients with peritoneal inflammation, as a result of infection with Staphylococcus epidermidis, the levels of sIL-6Rα correlate with expression of chemokines and the recruitment of neutrophils and monocytes [44]. Moreover, mice engineered to express soluble gp130, which blocks IL-6 trans-signaling, have defective inflammatory responses characterized by decreased infiltration of neutrophils and monocytes to the site of inflammation [45]. The role of IL-6 in directing recruitment of inflammatory cells is not limited to its effects on neutrophils. Using a model of peritoneal inflammation, previous work revealed that in addition to augmenting the production of a number of chemokines, including CXCL10, CCL4, CCL5, CCL11, and CCL17, IL-6 modulates the expression of multiple chemokine receptors on infiltrating T cells [46]. IL-6 also plays a key role in activation of CD62 ligand-mediated adhesion during fever-range thermal stress, revealing another mechanism by which this cytokine influences T cell recruitment during inflammation [47]. Collectively, these studies demonstrate that IL-6 controls the shift between the recruitment of neutrophils and monocytes to sites of inflammation.

Given that IL-6 has a prominent role in mediating inflammation at local sites, it is not surprising that gp130 and its cognate cytokines play critical roles in protective immunity and immunoregulation during infection. Thus, mice that have a conditional deletion of gp130 in hematopoietic cells and hepatocytes are more susceptible to viral and bacterial pathogens [7]. Analysis of gp130 family cytokine-specific knockout mice provides a more detailed insight into the roles of these cytokines during infection-induced inflammation. Multiple studies have shown that IL-6 is required for resistance to many pathogens, including Candida albicans, Toxoplasma gondii, Listeria monocytogenes, and vaccinia virus [48–52]. For many of these organisms, the increased susceptibility to infection is associated with deficient neutrophil responses and increased pathogen loads, further highlighting the central role of IL-6 in controlling the recruitment of neutrophils during inflammation and thereby, influencing the resolution of infection.

Consistent with its role in regulating neutrophil responses, IL-6 can promote the production of IL-17 by NK and T cells, which in turn, promotes neutrophil mobilization and recruitment in multiple models of infection [53–55]. It has emerged recently that IL-6 is a critical factor in the generation of a subset of CD4⁺ T cells that produces IL-17, Th17 [56]. IL-6 promotes the development of these cells through STAT3-mediated up-regulation of the lineage-specific transcription factor retinoic acid-related orphan receptor (RORγt) and induction of IL-21, another cytokine that can drive Th17 responses [57–60]. IL-23, which is part of the IL-12 family of cytokines and shows structural homology to IL-6, can also drive Th17 responses [61]. Nonetheless, these studies reveal an indirect way that IL-6 influences neutrophil recruitment during inflammation. Although IL-17 is important in resistance to some pathogens, this cytokine and its associated CD4⁺ T cells are pathogenic in several models of autoimmunity, which will be discussed in greater detail below.

gp130 regulates B cell responses

IL-6 was identified initially as a B cell growth factor, and subsequent studies have revealed the ability of multiple gp130 signaling cytokines to induce proliferation of B cells [62–65]. Consistent with these observations, mice with mutations in gp130-mediated signaling and specifically, IL-6-deficient mice generate defective antibody responses [51, 66, 67]. Additionally, mice that overexpress IL-6 develop plasmacytosis characterized by elevated production of IgG1 [68]. Although the antibody defects in vivo are consistent with a role for gp130 as a B cell maturation factor, more recent studies have highlighted the contribution of IL-6 to the development of CD4⁺ T cells that provide the help required for optimal antibody production [69]. Indeed, a subset of CD4⁺ T cells, called T follicular helper cells (Tfh), has been identified that expresses the chemokine receptor CXCR5, which acts to direct these cells to follicles to provide help to B cells [70–72]. Within the follicles, Tfh cells promote germinal center reactions and the generation of high-affinity antibodies [73]. The link of gp130 to these events was established by reports indicating that IL-6 was required for the generation of Tfh cells and that CD4⁺ T cells activated in the presence of IL-6 up-regulate expression of the transcription factor Bcl6, the master regulator of Tfh cell development [69, 74]. Independently of its role in mediating Tfh differentiation, IL-6 promotes the ability of CD4⁺ T cells to produce IL-21, a potent inducer of B cell proliferation and class-switching [75–78]. Collectively, these studies demonstrate that IL-6 is a critical regulator of the interactions between CD4⁺ T cells and B cells during inflammation and that manipulation of this pathway could be important for development of vaccines or therapies targeting antibody-mediated autoimmune disorders.

Anti-inflammatory properties of gp130

IL-27 is a newer member of the gp130 family of cytokines, and initial studies highlighted its ability to promote Th1 responses, consonant with its structural similarity to IL-12 [79]. However, it is now clear that IL-27 can also act as an antagonist of multiple types of inflammation. Thus, mice lacking the IL-27Rα (WSX-1) are more susceptible to numerous intracellular infections, including T. gondii, Leishmania donovani, Mycobacterium tuberculosis, and Trypanasoma cruzi [80–83]. In each case, the IL-27R-deficient mice control the pathogen, but they also develop a T cell-mediated hyperinflammatory response. The ability of IL-27 to block T cell activation is not limited to Th1 responses, as multiple reports have shown that IL-27 modulates Th2 and Th17 responses, indicating that this cytokine has the ability to constrain T cell responses in an array of inflammatory settings [79]. Additionally, IL-27 can block the production of IL-2, a key T cell growth and survival factor, and several studies have identified a role for IL-27 and IL-6 in promoting the production of the key anti-inflammatory cytokine IL-10 from T cells [84]. Collectively, these studies reveal that IL-27 serves as a prominent inhibitor of inflammation through direct and indirect mechanisms.

Despite their use of shared receptors and signaling pathways, the studies described above contrast the proinflammatory effects of IL-6 with the inhibitory activities of IL-27. Although the mechanism underlying the ability of each cytokine to have pro- or anti-inflammatory effects is unclear, multiple studies have demonstrated that IL-6 can have anti-inflammatory properties in some circumstances. For example, in the absence of SOCS3, IL-6 acquires the ability to block proinflammatory cytokine production from TLR-activated macrophages [41, 42]. Furthermore, in cells engineered to express gp130, which does not interact with SOCS3, the resulting, sustained, gp130-mediated activation of STAT3 activates an anti-inflammatory response that is normally associated with IL-10 signaling [85]. These studies suggest that the duration of signaling through gp130 profoundly influences biological outcomes. Thus, abbreviated, IL-6-mediated STAT3 activation is proinflammatory, and sustained STAT3 signaling may change the function of the cytokine (Fig. 2). Nevertheless, the large body of work characterizing the role of the gp130 signaling cytokines during inflammation implicates this receptor as a prominent factor in balancing pro- and anti-inflammatory responses.

gp130 IN AUTOIMMUNITY AND ALLERGIC AIRWAY INFLAMMATION

It has been clearly established that inflammation is critical in the development of protective immunity to pathogens, and as highlighted in the previous section, this process must be tightly controlled to ensure proper resolution and prevent development of immune pathology in the host. Aberrant inflammatory reactions directed toward self- or environmental antigens can lead to the development of autoimmunity or nonspecific tissue damage. A number of studies have confirmed the role of gp130 and specifically, IL-6 in many instances in contributing to the progression of autoimmunity in a variety of settings. In this section, we will focus on 3 major organ systems: the CNS, the lungs, and the joints.

EAE: balancing the pro- and anti-inflammatory properties of gp130

EAE is characterized by demyelination and the accumulation of pathogenic CD4⁺ T cells in the CNS and has been used as an experimental murine model of MS and autoimmune neuroinflammation. Although there are conflicting reports about which cells are the primary mediators of disease in this setting, there is strong evidence that Th17 cells contribute to pathology [86–88]. As mentioned previously, the generation of this subset of CD4⁺ T cells is dependent on TGF-β and IL-6 or the IL-6-inducible cytokine IL-21 [57–60, 87, 89]. Accordingly, several studies have identified elevated levels of IL-6 and IL-17 in lesions from MS patients, and transfer of Th17 cells can exacerbate disease in animal models [61, 90, 91]. Additionally, IL-6-deficient mice are resistant to the development of EAE, demonstrating the pathological role of IL-6 in this setting [92–95]. Of relevance to this review, several studies have identified a role for IL-27 in limiting the expansion of Th17 cells during chronic inflammation and highlight the opposing roles of IL-6 and IL-27 on the generation of Th17 cells [96–98]. Notably, IL-27p28- or WSX1-deficient mice develop more severe EAE as a result of enhanced Th17 responses, demonstrating the significance of this pathway in disease development [96, 98]. However, TGF-β- and IL-6-driven Th17 cells produce the anti-inflammatory cytokine IL-10 and are therefore less pathogenic in EAE compared with IL-23-driven Th17 cells [99]. Collectively, these studies suggest that although gp130-mediated signals are critical in the establishment of Th17 fate, cytokines that use this receptor can limit the pathogenicity and generation of these cells directly.

IL-6, in concert with TGF-β, drives the differentiation of Th17 cells, whereas activation of CD4⁺ T cells in the presence of TGF-β alone leads to the development of FoxP3⁺ Tregs. The role of IL-6 in mediating the reciprocal developmental pathways of these 2 cell populations has clear relevance in EAE, where Th17 cells are pathogenic, and Tregs are protective [57, 100, 101]. Multiple studies have highlighted defects in Treg populations in patients with MS. It has been reported that these patients have fewer numbers of circulating FoxP3⁺ Tregs, which are less able to suppress T effectors in coculture assays [102–105]. In EAE, 1 report indicated that Tregs accumulate in the CNS but fail to control inflammation [100]. Consistent with a previous study identifying a role for IL-6 in blocking Treg-mediated suppression, activated T cells in the CNS were resistant to suppression by Tregs as a result of IL-6 [106]. Moreover, IL-6-deficient mice or mice lacking gp130 specifically on T cells are resistant to EAE induction, as they develop diminished Th17 responses and instead, generate a response dominated by CD4⁺ FoxP3⁺ Tregs [57, 107]. In the EAE model, IL-6 is the dominant cytokine that impacts the balance between proinflammatory Th17 cells and anti-inflammatory Tregs; however, other studies revealed that Tregs express the IL-27Rα WSX-1 [108]. Furthermore, IL-27 has the ability to block the development of FoxP3⁺ CD4⁺ T cells in vitro, although it remains unclear whether IL-27 impacts Treg development or function in vivo during EAE [109, 110]. In total, these studies highlight the direct role that gp130 plays in mediating the balance between protective and pathogenic properties of Th17 cells, as well as the balance of Th17 and Treg differentiation during EAE.

Lung inflammation: gp130 as a disease modifier during asthma

Asthma is a chronic inflammatory condition of the lungs characterized by maladaptive Th2 and Th17 responses. Multiple gp130 signaling cytokines have been linked to the development of allergic asthma and the extensive remodeling of the lung that can occur in severe disease. In support of this idea, there are several reports that describe the presence of elevated levels of IL-6 and the sIL-6Rα (which would promote trans-signaling) in a wide range of conditions that affects the lungs, including asthma, pulmonary hypertension, COPD, and bronchopulmonary dysplasia [111–116]. IL-6 can also promote the differentiation of Th2 cells, and experimental models of asthma have revealed the contribution of IL-6 to the recruitment of eosinophils and local mucus production [117–122]. IL-6 has been linked to pulmonary fibrosis remodeling in the lung, and overexpression of IL-6 in the airways of transgenic mice results in subepithelial cell fibrosis and airway thickening [123–127]. These latter effects may be explained by the ability of IL-6 to promote myofibroblast proliferation [128]. Similarly, OSM and IL-11 have some overlapping functions with IL-6 in allergic airway inflammation and may also contribute to disease progression. For example, OSM can stimulate collagen production and proliferation of mouse lung fibroblasts, and overexpression of OSM induced eosinophilia and lung fibrosis, characterized by increased collagen deposition and infiltration of lymphocytes [129, 130]. Additionally, targeted overexpression of IL-11 in the lungs of mice resulted in airway remodeling, subepithelial fibrosis, and inflammatory cell infiltration [131]. Collectively, these studies implicate IL-6, OSM, and IL-11 as disease modifiers during asthma but also illustrate the influence of gp130 on many aspects of the physiological response to tissue injury.

The role of IL-6 during allergic airway hyper-reactivity is analogous to its role in EAE, where it has been implicated in mediating the balance between Th17 cells and Tregs. Thus, blocking IL-6 in several murine models of asthma resulted in enhanced Treg numbers and diminished Th17 responses, associated with reduced pathology [132, 133]. However, perhaps not surprising, given the pleiotropic effects of these cytokines, there are also experimental data that suggest a protective role for IL-6 in this setting [134]. Nevertheless, the preponderance of studies indicating a pathogenic role for IL-6 in the development of asthma suggests that IL-6 inhibitors may be useful therapeutically, although this possibility has yet to be tested formally in patients (Fig. 3).

Figure 3. gp130 family cytokines are highly pleiotropic.

Despite the shared use of a receptor, gp130 family cytokines have several overlapping and opposing functions. IL-6, IL-11, and OSM (A–C) can promote fibrosis and osteoclastogenesis, and IL-27 blocks the differentiation of osteoclasts (D). Alternatively, IL-6 and IL-11 have been linked to proliferation of cancer cells, and OSM and IL-27 block proliferation of these cells. In the context of autoimmunity, IL-6 is a critical differentiation factor for Th17 cells and can promote Th2 differentiation, and IL-27 is a prominent inhibitor of multiple T cell subsets. Despite this anti-inflammatory ability, IL-27 can promote antitumor immunity in several cancer models (D). Understanding the factors regulating context-dependent harmful versus beneficial outcomes of gp130-mediated signaling is important, considering the interest in manipulation of these pathways therapeutically.

As noted previously, maladaptive Th2 and Th17 inflammatory responses are integral to the pathogenesis of allergic asthma, and there is a large body of work indicating that IL-27 is a potent antagonist of these T cell subsets [79, 84]. Consistent with those findings, in one model of asthma, the absence of the IL-27R resulted in exacerbated lung pathology, characterized by increased goblet cell hyperplasia, pulmonary eosinophil infiltration, and elevated serum IgE levels [156]. More recently, the ability of invariant NKT cells to limit Th2 responses in experimental asthma was linked to their production of IL-27 [157]. For humans, there is a paucity of studies that has examined the possible role of IL-27 in asthma; however, single nucleotide polymorphisms in IL-27p28 in different populations have been linked to increased susceptibility to asthma and COPD [158, 159]. In total, these studies demonstrate that during allergic airway inflammation, IL-6, IL-11, and OSM may have overlapping, pathological mechanisms, and IL-27 may be protective and highlight the central role of gp130 as a modifier of disease progression.

RA: demonstrating therapeutic potential of targeting IL-6

RA is a chronic, autoinflammatory disorder that is characterized by inflammation and swelling of the joints, as well as destruction of cartilage and bone tissue. The first link of gp130 to the pathogenesis of RA was provided by the observation that elevated levels of IL-6 can be found in the serum and synovial fluid of RA patients [27]. The sIL-6Rα, associated with trans-signaling, is also found in the synovial fluid of RA patients, and IL-6 trans signaling induces the formation of osteoclasts, a cell type that is important in RA, as it mediates bone resorption [135–137]. Additionally, a mutation in the IL-6 promoter region is associated with an earlier age of disease onset, and the concentrations of IL-6 and its soluble receptor in the synovial fluid correlated positively with disease score and joint destruction [136, 160]. In experimental settings, IL-6-deficient animals are resistant to the development of RA [161]. Conversely, gp130 Y759 mutant mice, which have sustained signaling through gp130, develop autoimmune arthritis spontaneously, characterized by accumulation of activated T cells and myeloid cells, which is dependent on IL-6 and STAT3 [162, 163]. These studies demonstrate the prominent role of IL-6 and gp130 in driving pathology associated with inflammation of the joints.

Like IL-6, OSM is expressed in the synovial fluid of patients with RA, and its capacity to act as growth factor for fibroblasts suggests it might play an important role in tissue remodeling [140–143]. Indeed, OSM has the capacity to stimulate synovial fibroblasts to proliferate and produce IL-6, MCP-1, and the chemokine CCL13, suggesting it might contribute to recruitment of inflammatory cells during disease progression [144, 145]. Accordingly, adenoviral-mediated overexpression of OSM in joints of WT mice results in inflammation, characterized by infiltrating mononuclear cells, synovial hyperplasia, and destruction of cartilage [164]. Similarly to OSM, administration of rIL-11 during induction of experimental arthritis resulted in enhanced inflammation, which correlated with increased mitogenesis of synovial fibroblasts. Conversely, IL-11R-deficient mice developed less-severe arthritis than WT controls in the same system [138]. IL-11, like IL-6, can also promote osteoclastogenesis [139]. However, there are conflicting reports about the role of IL-11 during experimental arthritis, and some reports have identified anti-inflammatory functions for this cytokine [165]. One study demonstrated that administration of IL-27 during a collagen-induced arthritis model attenuated disease progression significantly, which correlated with reduced Th1 and Th17 responses, consistent with the ability of this cytokine to limit aberrant T cell responses [166]. Alternatively, the improvement in disease course could be a result of the ability of IL-27 to block osteoclastogenesis [155]. In total, these studies indicate that several gp130 signaling cytokines have direct and indirect effects on the development of arthritis and suggest that they may serve as viable targets for the treatment of RA. Indeed, the development of humanized mAb against IL-6 has been remarkably successful in the treatment of RA for patients who do not respond to traditional therapies [167].

gp130: MEDIATING THE BALANCE BETWEEN INFLAMMATION AND CANCER?

The sections described above focus on the role of gp130 in the development of inflammatory processes and how this impacts autoimmunity; however, aberrant inflammation is also associated with the development of cancer. The link between these two processes has been noted for over 1 century, and it is now well established that several viral and parasitic infections are associated with the development of neoplastic disease [168]. Inflammatory cells are found in biopsies of malignant tissues in a wide variety of cancers, and in experimental settings, overexpression of inflammatory cytokines or adoptive transfer of inflammatory cells can increase the risk of cancer [169, 170]. Furthermore, the use of nonsteroidal, anti-inflammatory drugs reduces the rates of incidence and mortality significantly in many cancers, including prostate, breast, and colon [170]. Together, these studies highlight the links between inflammation and cancer and suggest that understanding the immune factors that promote oncogenesis may represent viable therapeutic targets.

The mechanisms that underlie the relationship between inflammation and cancer have remained relatively unexplored until recently, but several cytokines have been shown to play important roles during neoplastic disease. For example, in the last decade, it has been established that IL-12 and IL-23, 2 cytokines that are structurally related to IL-6 and IL-27, have opposing roles in the development of cancer [28, 171, 172]. Relevant to this review, there is good evidence that gp130 has diverse roles in cancer and that elevated levels of IL-6 can correlate with increased risk of developing certain cancers [173]. Therefore, the aim of this section is to discuss multiple aspects of the link between gp130 and cancer, focusing specifically on the role of dysregulated, gp130-mediated signaling in cancer progression and the antitumorigenic properties associated with this receptor.

Dysregulated, gp130-mediated signaling contributes to cancer

Gastric cancer and CRC are associated with aberrant inflammation of the mucosa, and gp130 has a well-characterized role in both settings for mediating disease progression. gp130 Y757F mice, which have a mutation in the SOCS3-binding site of gp130, provide the clearest and best-characterized example of gp130 signaling in mediating development of gastric cancer. These mice develop lymphadenopathy, splenomegaly, and gastric hyperplasia spontaneously [38]. The basis for this phenotype is complex, but it appears that the enhanced ability of IL-11, not IL-6, to activate STATs promotes cancer [174–176]. Collectively, these studies highlight the role of IL-11-mediated activation of STAT1 and STAT3 in mediating development of cancer in the gastric mucosa. The relevance of this model was confirmed in patients with gastric cancers, where overexpression of IL-6 and IL-11 correlated with increased phosphorylation of STAT3 in primary tissue biopsies [177]. Mutations in gp130 have also been identified in humans. Specifically, recent work demonstrated that 60% of IHCA are associated with in-frame somatic mutations in gp130 [178]. These mutated gp130 receptors constitutively signal, even in the absence of ligand, and the IL-6 target genes—serum amyloid A and C-reactive protein—are overexpressed in IHCA. Even the IHCA from patients with no mutation in gp130 revealed overexpression of gp130 protein, underscoring the importance of this receptor in this disease.

Although IL-11 is the more critical cytokine in driving gastric cancer, multiple studies have established that IL-6 contributes to the development of cancer associated with colitis. Importantly, patients that have dysplasia associated with ulcerative colitis have increased levels of IL-6 and phosphorylated STAT3 in tissue biopsies, and elevated levels of IL-6 are found in the serum of patients with CRC as well as murine models of colitis-associated colon cancer [179–181]. Furthermore, recent work revealed that IL-6 trans-signaling was critical in preventing apoptosis and promoting proliferation and cell-cycle progression in colitis-associated epithelial neoplasias [182–184]. This report and others suggest that dysregulation of SOCS3 and increased levels of STAT3 activation would contribute to the development of cancer in multiple neoplasias, including cholangiocarcinoma, hepatocellular carcinomas, and breast and lung cancer [185–188].

Antitumorigenic properties of gp130

Although there is a significant body of work suggesting that gp130-mediated signaling may be critical in development of cancer, there are reports demonstrating the ability of some gp130 family cytokines to block tumor progression. Multiple studies have highlighted the ability of OSM to block proliferation of several cancer cell lines, and the finding that the OSM receptor is methylated in cells from patients with CRC and melanoma suggests that loss of responsiveness to OSM might contribute to tumorigenesis [146–149]. Other reports identified that IL-27 also has antitumorigenic properties. For example, treatment of melanoma cells with IL-27 blocks proliferation, and overexpression of IL-27 in lung cancer cells suppresses cellular migration and invasion [150, 151]. Additionally, overexpression of IL-27 resulted in the increased clearance of multiple tumor strains in mice associated with enhanced antitumor CD8⁺ T cell and NK cell responses [152–154]. A murine model of neuroblastoma, where the oncogenic cells were engineered to express the IL-27R WSX-1, also displayed enhanced antitumor CD8⁺ T cell responses, and WSX1^−/− mice inoculated with murine B16 melanoma generate defective antitumor CD8⁺ T cell responses [189–191].

Collectively, the studies presented in this section emphasize the broad range of biological effects of gp130-mediated signaling in cancer. gp130-mediated activation of STAT3, by a cognate cytokine or somatic mutation, is oncogenic and contributes to disease progression in several models of cancer, and OSM and IL-27 are antitumorigenic. No reagents blocking gp130 cytokines or signaling specifically have been used successfully to treat cancer, but the literature underlining the oncogenic potential of STAT3 suggests that inhibitors will be useful in the clinic. Indeed, anti-IL-6 therapy has been successful in the treatment of Castleman's disease, a lymphoma-like disorder characterized by the overproduction of IL-6 [192]. The body of work presented here validates this cytokine family as targets for the development of new therapeutic regimens.

CONCLUSIONS

Much of the work on the gp130 cytokine family highlights the balance that exists between the pro- versus anti-inflammatory and protective versus pathogenic properties of gp130, and some studies have provided insight into how this process might be controlled. As described previously, the loss of SOCS3, naturally or in experimental systems, has a significant impact on the biological properties of gp130-initiated signals. Other mechanisms for this functional dichotomy might include tightly regulated expression of cytokine-specific receptor α chains or activation of various combinations of STAT molecules in response to different gp130 signaling cytokines. For example, the ability of IL-6 to activate primarily STAT3 homodimers, while IL-27 activates STAT3:STAT1 heterodimers, may partially explain differences in downstream effects. Although the biological properties of IL-6 are dependent on STAT3 in many cases, STAT3-deficient cells that are stimulated with IL-6 up-regulate a gene expression program normally associated with type I IFN signaling [193]. These observations indicate that the type of response generated downstream of each gp130 family cytokine is a consequence of the combination of STAT molecules that are activated. Understanding the factors that regulate context-dependent beneficial versus harmful outcomes of gp130-mediated signaling will be of critical importance if the intracellular signals are going to be targeted therapeutically.

Because of the ability of gp130 to influence inflammation in many different settings, it is an attractive target for therapies in cancer and autoimmunity. To that end, therapies designed to block IL-6, using a humanized antibody, have been successful in the treatment of a number of inflammatory conditions, including RA and Crohn's disease [167, 194]. In parallel with the emerging literature indicating a role for sIL-6R in mediating some of the pathogenic effects of IL-6, reagents have been developed that limit IL-6 trans-signaling specifically [195]. Despite the success of using anti IL-6 mAb and the continued interest in manipulation of gp130 signaling during inflammation, questions remain about the negative side-effects of these types of treatments. As a result of its role in promoting resistance to pathogens, therapies targeting gp130 might leave patients vulnerable to opportunistic infections but would not necessarily promote increased susceptibility to cancer, as has been observed with anti-TNF [196]. Although it has yet to be tested, treatment with IL-27 may prove therapeutically beneficial in some settings as a result of its ability to inhibit a broad array of T cell responses, but this ability might be compromised during treatment with reagents designed to block gp130 [79]. Thus, any therapies targeting gp130 will have to take into account its role in many biological processes.