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. Author manuscript; available in PMC: 2013 May 1.
Published in final edited form as: Semin Nephrol. 2012 May;32(3):287–294. doi: 10.1016/j.semnephrol.2012.04.008

Retinoid and TGF-β families: Crosstalk in development, neoplasia, immunity and tissue repair

Qihe Xu 1, Jeffrey Kopp 2
PMCID: PMC3407374  NIHMSID: NIHMS374232  PMID: 22835460

Abstract

TGF-β isoforms are pro-fibrotic cytokines, par excellence, and have complex, multifunctional effects on many systems, depending on the biologic setting. Retinoids are vitamin A derivatives that also have diverse effects in development, physiology, and disease. The interactions between these classes of molecules are, not surprisingly, highly complex and are dependent upon the tissue, cellular, and molecular settings.

Introduction

TGF-β isoforms and retinoids regulate many biologic processes, and the interactions between these molecules have been studied for many years. Two decades ago, Roberts and Sporn reviewed interactions between these two superfamilies1. This review will provide an update on particular aspects of the molecular crosstalk and their relevance in development, neoplasia, the immune system, tissue repair and the kidney. Our belief is that insights into interactive pathways in other settings may be worth exploring in nephrology research.

Retinoids are a family of vitamin A metabolites or analogs, including (i) natural provitamin A, vitamin A, and other retinoic acid precursors, which cannot bind retinoid nuclear receptors, but are characterized by their potential to be converted into retinoic acids; (ii) natural retinoic acids, including all-trans-retinoic acid (ATRA) and 13-cis-retinoic acid, which bind and activate retinoic acid receptors (RARs α, β and γ), and 9-cis-retinoic acid, which binds and activates both RARs and retinoid X receptors (RXRs α, β and γ); and (iii) synthetic retinoids, which bind one or more RAR or/and RXR isotypes and exert agonistic or antagonistic actions2.

As the major functions of retinoids are RXR/RAR–dependent, conversion of vitamin A into retinoic acids is largely a process of vitamin A activation. This involves two oxidation steps, catalyzed by alcohol dehydrogenases (ADHs 1–4) and retinaldehyde dehydrogenases (RALDHs 1–3), respectively. While the first step is reversible, the RALDH-driven second step is not. Eventually, following catalysis by cytochrome P450 enzymes Cyp26A, B and C, retinoic acids can be converted into metabolites with reduced capacity to activate the canonical RXR/RAR pathway2.

It has been said that TGF-β is like a switch that turns some systems on and other systems off and sometimes turns the same switch on or off, depending on the context (Michael Sporn, personal communication). Thus TGF-β can have opposite effects depending on the physiologic (developmental state, age, organ system, cell type, species) or pathologic setting. With this in mind, it is perhaps not surprising that retinoid/TGF-β interactions are also complex.

Molecular basis of retinoid/TGFβ crosstalk

TGF-β signaling via SMADs and other pathways and retinoid signaling via nuclear receptors intersect in complex ways that are frequently cell and context-dependent. First, there is shared repression. TGIF (TG-interacting factor) is a transcriptional corepressor of SMAD signaling, that inhibits access of co-activators to phosphorylated SMADs (pSMADs). TGIF is also a co-repressor for RXR-α, in part by recruiting the general co-repressor C-terminal binding protein (CtBP) and suppressing RXR-α mediated transcription (Bartholin, 2006). Thus, TGIF inhibits both TGF-β- and retinoid-driven gene transcription.

Second, retinoids may suppress TGF-β signaling. It was reported that ATRA suppresses the TGF-β superfamily member BMP4 by enhancing ubiquitin-mediated degradation of pSMAD1; future studies might address whether similar mechanisms are operative in TGF-β signaling3. With similar action but via a secreted mediator, 9-cis-retinoic acid suppresses TGF-β-mediated induction of several pro-fibrotic molecules, e.g., fibronectin and plasminogen activator inhibitor-1 (PAI-1), in cultured human mesangial cells and this effect is mediated by the stimulation of hepatocyte growth factor4. In isolated heart tissue and in cultured NIH-3T3 fibroblasts, ATRA increases TGF-β stimulated pSMAD2 and pSMAD3, but decreases nuclear accumulation of these transcription factors and decreases pSMAD-mediated transcriptional activity5.

Third, retinoids may amplify TGF-β signaling, via transcriptional and post-translational mechanisms. ATRA increases TGF-β transcript levels and TGF-β1 protein production by PC12 cells, acting on the TGF-β1 promoter6. In mesenchymal stem cells, ATRA induces SMAD RNA expression and protein nuclear localization7. In retinal pigment epithelial cells, ATRA increases expression of thrombospondin-1 and this in turn converts TGF-β1 to its active form8. ATRA induces production of TGF-β2 by pancreatic cancer cells in vitro, as discussed further below9.

Fourth, TGF-β may affect tissue levels of retinoid ligands and expression of nuclear receptors. For example, Alb/TGF-β1 transgenic mice have reduced tissue levels of retinoids10; TGF-β1 induces expression of RARs and RXRs in osteoblasts 11and inhibits Cyp26b1, a metabolizing enzyme of ATRA, in T cells12.

Embryonic and fetal development

Retinoids/RAR and TGF-β are involved in embryogenesis and organ development, with significant crosstalk between the two pathways1317. Retinoids and TGF-β also have crosstalk in embryonic stem cells. In embryonic stem cells, ATRA induces the expression of Foxa1, which acts as a pioneer transcription factor, binding and poising chromatin for intersection with the TGF-β-induced SMAD signaling, and cooperates with the latter in de novo activation of α-fetoprotein gene expression17. In C2C12 mouse myoblasts, both ATRA and 9 cis-retinoic acid are potent inhibitors of the anti-myogenic effect of TGF-β1, likely through a SMAD-independent mechanism18.

Vitamin A is required for normal organogenesis, including the heart and other tissues. Vitamin A-deficient (VAD) quail embryos lack retinoic acids and are characterized by a grossly abnormal cardiovascular system that can be rescued by ATRA. In VAD embryos TGF-β2 mRNA and protein expression, as well as TGF-β receptor II are greatly elevated. Administration of TGF-β2-specific antisense oligonucleotides or an antibody specific for TGF-β2 to VAD embryos normalizes posterior heart development and vascularization, while the administration of exogenous active TGF-β2 protein to normal quail embryos mimics the excessive TGF-β2 status of VAD embryos and induces a VAD cardiovascular phenotype. In VAD embryos pSMAD2/3 and pErk1 are not activated, while pErk2 and pcRaf are elevated and pSMAD 1/5/8 are diminished. Thus, in the early avian embryo TGF-β2 has a major role in the retinoic acid-regulated posterior heart morphogenesis for which it does not use SMAD2/3 pathways, but may use other signaling pathways19. Retinoic acid/RXR-RAR regulation of TGF-β2 in developing heart is evolutionarily conserved as RARα1/RARβ−/−, RARα1/RXRα−/− and RXRα−/− mice also show increased TGF-β2 expression and defects in the differentiation of the second heart field and heart outflow tract septation defects20,21

In the developing lung, it appears that endogenous ATRA acts as a major regulatory signal integrating Wnt and TGF-β pathways in the control of Fgf10 expression during induction of the mouse primordial lung, inhibiting TGF-β signaling22, while activating Wnt signaling through local repression of its antagonist, Dickkopf homolog 1 (Dkk1)23. In addition, TGF-β2 is required for the development of pancreatic and cerebral cortex; administration of excess ATRA before neurulation inhibits TGF-β2 expression in pancreas and brain and disrupts morphogenesis of pancreas and cerebral cotex24,25. TGF-β3 is required for chondrocyte differentiation, which is suppressed by ATRA. It is now known that ATRA/RAR suppresses chondrogenesis through suppressing SMAD2 and SMAD3 phosphorylation, increasing Smad7 expression and TGIF26,27.

Either excess or deficiency of retinoic acid during a critical stage of inner ear development can produce teratogenic effects. In utero exposure of the developing mouse inner ear to a high dose of ATRA results in severe malformations of the inner ear that are associated with diminished levels of endogenous TGF-β1, TGF-β type II receptor and Smad2 in the inner ear, while suppression of RARα expression by an antisense oligonucleotide leads to a reduction in endogenous TGF-β1 and a marked suppression of chondrogenesis, which can be partially rescued by exogenous TGF-β1. Thus, TGF-β1 may play important roles in the physiologic and pathologic effects of RA on inner ear development28.

Retinoid/TGF-β crosstalk may contribute to kidney development but a definitive role remains to be established. In the induction of avian pronephros (the first kidney to arise in development), the neural tube releases TGF-β family member activin, and competence of the intermediate mesoderm cells to respond and differentiate appears to be driven by retinoic acid-dependent expression of Hoxb4, a critical transcription factor29. RXR/RAR-mediated canonical transcriptional activity is predominantly located in the ureteric bud lineage of the pre- and post-natal kidneys30 and mice with specific deletion of TGF-β type II receptor from the ureteric bud lineage develop grossly normal kidneys do not support indispensable crosstalk between the two pathways in the ureteric bud31.

Neoplasia

Retinoids are approved for promyelocytic leukemia; acting as a differentiating agent, it has substantially improved patient outcomes. In HL-60 human promyelocytic leukemia cells, TGF-β1 enhances ATRA-induced suppression of cell proliferation and inhibits ATRA-induced apoptosis32; while ATRA directs differentiation to granulocytes in a RAR-dependent manner, TGF-β SMAD2/3-dependently directs differentiation to monocytes; simultaneous treatment of these cells with TGF-β1 and RA, which leads to almost equal numbers of granulocytes and monocytes, significantly reduced the level of phospho-Smad2/3 and its nuclear accumulation, compared with that in cells treated with TGF-β1 alone33. ATRA also reduces expression of microRNA-146A in an acute promyeloctyic cell line; this microRNA targets SMAD4, and thus the effect is to increase TGF-β signaling34. ATRA also promotes differentiation of Wilms tumor cells, normalizing the expression of multiple genes associated with the neoplastic phenotype35.

Human concentrative nucleoside transporter-3 (hCNT3) is a sodium-coupled nucleoside transporter that exhibits high affinity and broad substrate selectivity, making it the most suitable candidate for mediating the uptake and cytotoxic action of most nucleoside-derived drugs. The drug of this class most commonly used in the treatment of chronic lymphocytic leukemia (CLL) is the pro-apoptotic nucleoside analog fludarabine (Flu), which enters CLL cells primarily through human equilibrative nucleoside transporters (hENTs). Although CLL cells lack hCNT3 activity, they do express this transporter protein, which is located mostly in the cytosol. Interestingly, RA increases hCNT3-related activity through a mechanism that involves trafficking of pre-existing hCNT3 proteins to the plasma membrane. This effect is mediated by the autocrine action of TGF-β1, which is transcriptionally activated by ATRA in a p38-MAP kinase dependent manner36.

ATRA suppresses the expression of TGF-β1 and TGF-β-dependent growth of malignant pleural mesothelioma in a subcutaneous xenograft mouse model37, while inducing active TGF-β2 and suppressing Capan-2 and Hs766T human pancreatic cancer cells in a TGF-β-dependent manner9.

Immune system

The TGF-β family and the retinoid family molecules both function as immunomodulators3841. Although crosstalk between retinoids and TGF-β in immunity have long been suspected due to indirect evidence, such as their similar effects on cell growth and viral production, as well as RA induction of TGF-β and TGF-β receptor in HL-60 human promyelocytic leukemia cells1, direct evidence on such interactions has not appeared until the recent years42,43.

TGF-β is a master regulator of T cells and plays an indispensable role in immune tolerance39. Thus autoimmune inflammation was triggered by T cell-specific over-expression of a dominant negative mutant of TGF-β type II receptor44 and was observed in TGF-β1 knockout mice4547. TGF- β2 and TGF-β3 knockout mice did not show such a phenotype48,49, likely due to the predominant expression of TGF-β1 in the T cell lineage. It is currently believed that TGF-β is required for the development of CD8+ T cells, natural regulatory T cell (nTreg), natural Th17 cells (nTh17) and natural killer T (NKT) cells from CD4+CD8+ immature T cells in the thymus39,50. In the periphery, TGF-β is believed to suppress the functions of natural killer cells, CD8+ cytotoxic T lymphocytes, dendritic cells, macrophages and neutrophils51, while differently regulating inducible regulatory T cell (iTreg), Th1, Th2, and Th17 T helper cells, which are characterized by the expression of different transcription factors Foxp3, T-bet/STAT4, GAGA3/STAT6 and RORγt/STAT3, respectively52. In brief, TGF-β is indispensable for the development of Foxp3+ iTreg cells51, suppresses Th1 development53,54 and indirectly promotes Th17 development5355. Although development of Th1 and Th2 cells are both suppressed by TGF-β in vitro and promoted by partial TGF-β signaling attenuation in vivo, Th1 development is exclusively promoted when TGF-β signaling elimination is more complete, such as in TGF-β type II receptor knockout mice39. In TGF-β1 and/or TGF-β1 type II receptor knockout mice, due to loss of Treg cells, polarization of the Th1/Th2 axis to Th1, un-checked autoimmunity and/or over-response to weak immunogens, serum IgM, IgG and IgE antibodies are increased, in contrast to a significant reduction in serum IgA56,57. The latter is in keeping with the concept that TGF-β directly targets B cells to induce IgA production58,59.

TGF-β regulation of iTreg, Th1 and Th17 development involve both Smad-dependent and -independent pathways. Although Smad2 and Smad3 were shown to play redundant roles in regulating iTreg and Th1 development60, another study showed that selective deletion of Smad2 from the T lymphocyte linage led to slightly increased nTreg numbers in thymus and other lymphoid tissues, impaired TGF-β conversion of naïve T cells into iTreg cells, reduced Th17 differentiation both in vitro and in vivo and, importantly, ameliorated a model of experimental autoimmune encephalomyelitis61. Based on the effects of chemical inhibition and/or gene deletion of MAP kinase isotypes, it appears that ERK (e.g., ERK1) mediates iTreg cell development, p38 mediates Th17 development and JNK (e.g., JNK2) modulates both iTreg and Th17 development62.

Animal and clinical studies of vitamin A deficiency (VAD) and vitamin A supplementation indicate that vitamin A is required to defend against various infections, because VAD compromises functions of antigen presenting cells (APCs) and neutrophils, reduces total T cell and NKT cell numbers, increases Th1 and Th17 cells, reduces Th2 and Treg cells, as well as diminishing antibody-mediated immunity41,63. The thymus is known to express the synthetic enzymes and nuclear receptors necessary for a functional endogenous retinoid signaling, but the exact role for such an endogenous retinoid system in thymus remains poorly understood. Nevertheless, exogenous retinoids have been shown to act on thymocytes to suppress CD8+ development, enhance CD4+ development, increase total immature CD4+CD8+ cell number by preventing apoptosis, and increase egress of mature T cells from the thymus to augment total peripheral T cell numbers63.

In peripheral tissues, ATRA plays an important role in sustaining the stability and functionality of nTregs in the presence of inflammatory cytokines such as IL-664 and is required for bone marrow cells to differentiate into dendritic cells, which continue to synthesize ATRA to maintain the acquired phenotype and functions, including releasing ATRA to direct the differentiation and control gut-homing of T and B cells in a paracrine fashion40,65. It is not fully understood how ATRA synthesis is regulated in dendritic cells, but it appears that some pathogen-derived components, pro-inflammatory cytokines and Toll-like receptor (TLR) agonists up-regulate RALDH expression in dendritic cells40. The constitutive expression of RALDH2 in dendritic cells is critically dependent on the constitutive activation of the Wnt-β-catenin signaling pathway66 and pathogen infection can stimulate TLR2 on dendritic cells to promote RALDH2 expression and ATRA synthesis67. ATRA can directly promote maturation and activation of B cells and also indirectly regulate B cells through modulating T cells, differentially regulating IgA, IgG1, IgG2a, IgG2b, IgG3 and IgM responses. Specifically, B1 cells represent a distinct subset of B cells that produce most of the natural serum IgM and much of the gut IgA and function as an important component of early immune responses to pathogens. The development of B1 cells is severely impaired in mice fed on a VAD diet and enhanced by exogenous ATRA treatment. Thus, the ATRA-dependent pathway is critical for regulating B1-mediated humoral responses68. Importantly, ATRA regulates APCs and T cells in a cell type- and context-dependent manner63. ATRA treatment of APCs from different origins might lead to release of cytokines that either favor Th1 or Th2 response63. For example, although ATRA is known to directly target T cells, diverting TGF-β-induced Treg/Th17 balance toward Treg41,63, in the presence of IL-15, ATRA induces dendritic cells to release pro-inflammatory cytokines IL-12 and IL-23, which together with ATRA, suppress Treg development and promote Th1 and Th17 conversion69, indicating that ATRA regulation of Th1, Th17 and Treg developments is condition-dependent43. In addition, ATRA regulation of Th2 development is also condition-dependent, especially depending on the stage of T cell differentiation. Exposure of naïve T cells without initial activation to ATRA suppresses both Th1 and Th2 development, however, in naïve CD4 cells that have undergone initial activation in vitro, ATRA enhances Th2 development43. Different retinoid nuclear receptors might play different roles in immunomodulation. Using selective retinoid agonists or antagonists, RXR- and RAR-, especially RARα-, mediated mechanisms have been suggested in mediating ATRA regulation of the Th1/Th2 axis7073. RARβ and/or RARα have been suggested to play an important role in expression of homing receptors in T cells74. In contrast, data from RARγ knockout mice indicate that RARγ is required for CD8+ T cell response to Listeria monocytogenes infection and macrophage response to TLR stimulation, although it is dispensable for T and B lymphocyte development, humoral immune response and in vitro Th cell differentiation75.

In 2007, Mucida D, et al, first identified ATRA as a key regulator of the TGF-β-dependent Treg/Th17 axis, inhibiting RORγt-dependent induction of Th17 cells and promoting Foxp3-dependent Treg differentiation76. It has been shown that ATRA not only synergizes with TGF-β and IL-2 to induce Treg cells, but also make them more resistant to pro-inflammatory cytokines77. ATRA and TGF-β cooperate to promote foxp3 expression, not only in naïve T cells78, but also in differentiated CD4+ and CD8+ T cells79,80, highlighting a role for retinoid-TGF-β crosstalk in regulating the plasticity of T cells. Interestingly, ATRA synergizes with peroxisome proliferator-activated receptor (PPAR) α and γ agonists to promote TGF-β conversion of human CD4+CD25 T cells into functional Treg cells81, suggesting that they might regulate Treg development via distinct mechanisms. In keeping with this observation, PPAR agonists promote Foxp3 expression by inhibiting DNA methyltransferases and thus inducing demethylation of the Foxp3 promoter81, while ATRA augmentation of TGF-β-induced Treg development involves the binding of RAR and RXR to a dominant site in the enhancer I of the Foxp3 gene and a subordinate site in the promoter82. The latter leads to increased histone acetylation in the region of the Smad3 binding site and increased binding of pSMAD3, which is in contrast to the action of IL-27, i.e, inhibition of Foxp3 expression through binding of pStat3 to a gene silencer in another conserved enhancer region (enhancer II) downstream from enhancer I, leading to loss of pSMAD3 binding to enhancer I. Thus, control of accessibility and binding of pSmad3 provides a common framework for positive and negative regulation of TGF-β-induced Foxp3 transcription82.

In T cells, besides the effects of ATRA on the actions of TGF-β, it appears that TGF-β also affects the ATRA pathway through inhibiting Cyp26b1, a metabolizing enzyme of ATRA, thus sustaining ATRA-dependent signaling12. In follicular dendritic cells, where ATRA is abundant, however, ATRA activates RAR signaling and cooperates with TLRs to up-regulate secretion and activation of TGF-β183, which, together with ATRA, directly and synergistically targets B cells to induce IgA class switching in a Runx-dependent manner, although the detailed mechanism is still to be defined59. ATRA and TGF-β1 also have crosstalk upon regulating expression of gut-homing receptors on T cells, i.e., ATRA induces integrin α4β7 and CCR9; TGF-β induces integrin αEβ7; the combination of TGF-β and ATRA results in further up-regulation of both integrins α4β7 and αEβ7, but down-regulates the expression of CCR943.

Tissue repair: Cytoprotection and anti-fibrosis

Isotretinoin (13 cis-retinoic acid) is FDA-approved for nodular acne. Its favorable effects include reversing the pathogenic processes of follicular retention hyperkeratosis, sebaceous lipogenesis, inflammation, and bacterial colonization. It has been proposed that therapeutic benefit depends upon the export of the nuclear factor FOXO1 from the nucleus, which leads to suppression of transcription of genes encoding the androgen receptor, proliferative factors, lipid biosynthesis, and inflammatory cytokines84. This may serve as a paradigm for how retinoids may alter transcriptional networks in ways that alter cellular phenotype, restoring normal cellular function.

While model systems differ, the predominant theme is that retinoids suppress TGF-β production or signaling. Thus VAD is associated with increased TGF-β activity. VAD rat pups exhibit increased pulmonary alveolar basement membrane thickness by approximately two-fold, with increased fibrotic collagen; this was associated with increased production of TGF-β and reactive oxygen species85. ATRA inhibits TGF-β stimulation of pro-fibrotic molecules in cultured mesangial cells, including fibronectin and PAI-186. Similarly, ATRA inhibits TGF-β-driven liver fibrosis in a rat common bile duct ligation model87. TGF-β increases vascular endothelial growth factor (VEGF) production by cultured smooth muscle cells88 and endometrial cells; in the latter cells, this effect requires ATRA, which initiates a process whereby VEGF mRNA transcripts are directed toward larger, poly-ribosomes that are more translationally active89.

Under some circumstances, retinoids can enhance TGF-β activity. ATRA stimulates TGF-β production by neoplastic HL-60 cells (as noted above), stimulates TGF-β2 in mouse keratinocytes in vitro and in vivo90 and stimulates TGF-β production in cultured chondrocytes91 although it inhibits TGF-β production in cultured myocytes91.

In experimental kidney disease, ATRA has shown therapeutic effect in models with various degrees of inflammation and fibrosis, including Thy-1 rat glomerulonephritis (with down-regulation of TGF-β and TGF-β receptor II)92, the 5/6 nephrectomy rat model (with reduced TGF-β expression)93 and the mouse unilateral ureteral ligation model94. On the other hand, ATRA therapy ameliorates mouse MLR/lpr lupus model while increasing renal TGF-β expression and suppressing glomerular inflammation; the authors offered the interpretation that TGF-β was acting to suppress inflammation, although there was no demonstration that this was the critical pathway95. However, while Alb/TGF-β1 transgenic mice exhibit glomerulosclerosis and reduced renal tissue levels of ATRA, therapeutic administration of ATRA increased fibrosis and mortality, toxicity which may have been dose related10.

Conclusion

TGF-β and retinoid family members play major roles in development, neoplasia, immune response and immunologic disease, tissue repair, and fibrotic disease. As shown above, there is complex crosstalk between the TGF-β and retinoid signaling pathways. Various retinoids have been approved for therapeutic uses, including cancer and acne, with the common theme being promotion of cellular differentiation. Various retinoids with different affinities for particular RARs have been developed. As a class, retinoids hold considerable promise as therapeutic agents for human kidney disease, although no trials have been completed to date. There is compelling opportunity to harness retinoid activities, including interactions with TGF-β family members, to treat disease.

Table 1.

Mechanisms of crosstalk between retinoid and TGF-β families.

Effect Examples
Shared repression TGIF, a transcriptional co-repressor acting on SMADs and RXRα
Retinoids suppress TGF-β signaling
  • Ubiquitin-mediated SMAD4 degradation

  • Induce HGF production, antagonizing TGF-β activities

  • Decrease nuclear accumulation of SMADs

Retinoids increase TGF-β activity
  • Increase transcription of TGFB1 and TGFB2 genes.

  • Increase SMAD transcription and nuclear localization

TGF-β affects retinoid pathway
  • Induce RAR and RXR expression

  • Suppresses Cyp26b1 expression

  • Reducing tissue concentrations of ATRA

Legend. Retinoids affect TGF-β signaling either positively or negatively in a cell type- and context-dependent manner. TGF-β also regulates the retinoid signaling pathway at multiple levels. More details and references, see text.

Table 2.

Effects of retinoids and TGF-β on the immune system

Central functions, including direct
and indirect
Peripheral functions
TGF-β (some effects are isform dependent, with TGF-β1 playing a central role) Required: development of CD8+ T cells, natural regulatory T cell (nTreg), natural Th17 cells (nTh17) and natural killer T (NKT) cells from CD4+CD8+ immature T cells Essential: development of inducible regulatory T cell (iTreg)
Suppressive: development of Th1, Th2, NKT, CD8+ cytotoxic T cells, dendritic cells, macrophages, and neutrophils
Promoting: development of Th17 cells
Retinoids Physiologic retinoids: unknown
Exogenous retinoids: suppress CD8+ development, enhance CD4+ development, increase total immature CD4+CD8+ cell number, and increase egress of mature T cells from the thymus to augment total peripheral T cell numbers
Physiologic retinoids: decrease Th1 and Th7, increase Th2 and Treg; required for development of B1 cells, functions of neutrophils, antigen presenting cells (APC), humoral immune responses, as well as for maintaining total and NKT numbers
Exogenous retinoids: augment total peripheral T cell numbers, promote development of B1 cells and maturation and activation of B cells; condition-dependently regulate Treg, Th1, Th2 and Th17 development
Retinoids modulating TGF-β production or effect
  • Synergizes with TGF-β to promote nTreg differentiation

  • Cooperates with Toll receptors to stimulate TGF-β production

  • Synergizes with TGF-β to promote Treg resistance to inflammatory cytokines

  • Induces integrin α4β7 expression on T cells, while TGF-β induces αEβ7 expression on T cells, and the combination promotes gut homing

Legend. Shown are selected effects of TGF-β and retinoids on the immune system, as well as modulatory effects of retinoids on the actions of TGF-β on the immune system.

Acknowledgment

We thank Professor Randolph J. Noelle, King's College London, for his excellent comments on this manuscript. This work was supported in part by the NIDDK Intramural Research Program.

Grant Support: NIDDK Intramural Research Program and Kidney Research UK Innovation Grant

Footnotes

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