Selective regulatory function of Socs3 in the formation of IL-17-secreting T cells

Chen, Zhi; Laurence, Arian; Kanno, Yuka; Pacher‐Zavisin, Margit; Zhu, Bing; Tato, Cristina M.; Yoshimura, Akihiko; Hennighausen, Lothar; O’Shea, John J.

doi:10.1073/pnas.0600666103

Cited by 583 publications

(500 citation statements)

References 60 publications

Supporting

Mentioning

466

Contrasting

Unclassified

Order By: Relevance

“…It will be important to determine the mechanisms by which RAR␣ influences ROR␥t expression in CD4 ϩ T-cell differentiation. Although Stat3 and Stat5 are key regulators of Th17/Treg differentiation, 6,7,27,[32][33][34]41 our data indicate that ATRA appears to exert its effect independently of these factors. As a transcription factor itself, RAR␣ might directly bind the promoters of the Foxp3, Il17, and/or ROR␥ genes; in the latter case, the expectation would be that it serves as a repressor.…”

Section: Discussionmentioning

confidence: 83%

“…27,[32][33][34] Specifically, in the presence of TGF-␤1, IL-2 acting through Stat5 is known to increase FoxP3 and inhibit IL-17. In contrast, IL-6 acting through Stat3 increases IL-17 and inhibits FoxP3.…”

Section: The Effect Of Retinoids Is Independent Of Stat3 Stat5 and mentioning

confidence: 99%

“…Whereas AM580 was as effective as ATRA at increasing the percentage of FoxP3 ϩ cells, A7980 had little demonstrable effect, thus strongly implying a role for RAR␣ as the key player in FoxP3 expression. These data are also notable in that they imply a direct role for retinoids in controlling FoxP3, as the studies were performed using isolated T cells.The effect of retinoids is independent of Stat3, Stat5, and IL-2Several lines of evidence point to key roles for Stat5 and Stat3 as essential regulators of [32][33][34] Specifically, in the presence of TGF-␤1, IL-2 acting through Stat5 is known to increase FoxP3 and inhibit IL-17. In contrast, IL-6 acting through Stat3 increases IL-17 and inhibits FoxP3.…”

mentioning

confidence: 99%

See 2 more Smart Citations

Retinoic acid inhibits Th17 polarization and enhances FoxP3 expression through a Stat-3/Stat-5 independent signaling pathway

Elias

Laurence

Davidson

et al. 2008

Blood

Self Cite

394

333

View full text Add to dashboard Cite

IntroductionImmune responses are orchestrated by subsets of CD4 ϩ helper and effector T cells. Classically, differentiated T cells have been classified as belonging either to T-helper 1 (Th1) or Th2 lineages. 1 Th1 cells secrete interferon-gamma (IFN-␥) in response to interleukin-12 (IL-12) and require the transcription factors T-box21 (T-bet) and signal transducer and activator of transcription 4 (Stat4) 2 and Stat1, whereas Th2 cells secrete IL-4, IL-5, and IL-13 and require the transcription factors GATA-binding protein 3 (GATA-3) and Stat6. 3 While this simple paradigm was instrumental in understanding immune responses to model pathogens, it was less clear how such a model explained the pathogenesis of autoimmune disease.More recently, additional fates for CD4 ϩ T cells have emerged that provide more insights into the mechanisms of tolerance and immune-mediated disease. One of these new subsets of T cells, expressing the transcription factor FoxP3, is termed regulatory T cells (Tregs) and serves to inhibit immune responses. Deficiency of FoxP3 in mice and humans is associated with fatal autoimmune disease. 4,5 FoxP3 ϩ Tregs normally develop in the thymus, but FoxP3 expression and Treg function also develop when naive CD4 ϩ T cells are stimulated in vitro with transforming growth factor-␤1 (TGF-␤1) and IL-2. 6 Development and differentiation of Tregs and expression of FoxP3 are dependent upon another transcription factor, Stat5. 7,8 Another new subset of T cells that may be related to Tregs is a subset that produces the proinflammatory cytokine IL-17 (Th17 cells). Overproduction of IL-17 has been noted in a variety of models of autoimmune disease, including experimental autoimmune encephalomyelitis and collagen-induced arthritis. 9-13 Importantly, increased levels of IL-17 are also seen in human diseases, such as multiple sclerosis, rheumatoid arthritis, and inflammatory bowel disease. 14-16 Th17 cells are generated by the cytokines TGF-␤1 and IL-6, the latter of which acts via Stat3 to induce the transcription factor retinoic acid orphan receptor gamma (ROR␥t). 17 Overexpression of ROR␥t induces IL-17 production, whereas deficiency of this transcription factor virtually abrogates Th17 differentiation.ROR␥t belongs to a superfamily of retinoid nuclear receptors that include the retinoic acid receptors (RARs), retinoid X receptors (RXRs), and other RORs. 18 A connection between retinoids and CD4 ϩ T-cell differentiation has long been recognized. Memory T cells from vitamin A-deficient mice have been found to overproduce . 19 In contrast, administration of the active metabolite of vitamin A, retinoic acid (RA), has been reported to suppress memory cell IFN-␥ production and increase IL-4 secretion. 20 Later, it emerged that vitamin A can be metabolized into retinoic acid isomers with different ligand-receptor affinities: 9-cis retinoic acid, with a higher affinity for the RXR family, and all-trans retinoic acid (ATRA), with a higher affinity for the RAR family. 21 Acting through RXR␣, 9-cis retinoic acid skews n...

show abstract

Section: Discussionmentioning

confidence: 83%

Section: The Effect Of Retinoids Is Independent Of Stat3 Stat5 and mentioning

confidence: 99%

mentioning

confidence: 99%

See 1 more Smart Citation

Retinoic acid inhibits Th17 polarization and enhances FoxP3 expression through a Stat-3/Stat-5 independent signaling pathway

Elias

Laurence

Davidson

et al. 2008

Blood

Self Cite

394

333

View full text Add to dashboard Cite

show abstract

“…This subset is expanded and maintained by IL-23. Both IL-6 and IL-23 activate the transcription factor STAT-3, which directly binds to the IL-17 promoter to regulate IL-17 expression (32). Conversely, suppressor of cytokine signaling 3 negatively regulates Th17 differentiation by inhibiting STAT-3 phosphorylation (32,33).…”

mentioning

confidence: 99%

“…Both IL-6 and IL-23 activate the transcription factor STAT-3, which directly binds to the IL-17 promoter to regulate IL-17 expression (32). Conversely, suppressor of cytokine signaling 3 negatively regulates Th17 differentiation by inhibiting STAT-3 phosphorylation (32,33). In addition to STAT-3, retinoic acidrelated orphan receptor ␥t (ROR␥t) is an important transcription factor for initiation of Th17 differentiation (34).…”

mentioning

confidence: 99%