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TGF-β Promotes Th17 Cell Development through Inhibition of SOCS3

Hongwei Qin^*, Lanfang Wang, Ting Feng, Charles O. Elson^*,, Sandrine A. Niyongere^*, Sun Jung Lee^*, Stephanie L. Reynolds^*, Casey T. Weaver^,, Kevin Roarty^*, Rosa Serra^*, Etty N. Benveniste^* and Yingzi Cong^*,

^*Department of Cell Biology, Division of Gastroenterology and Hepatology, Department of Medicine, Department of Microbiology, and Department of Pathology, University of Alabama at Birmingham, Birmingham, AL 35294

TGF-β, together with IL-6 and IL-21, promotes Th17 cell development. IL-6 and IL-21 induce activation of STAT3, which is crucial for Th17 cell differentiation, as well as the expression of suppressor of cytokine signaling (SOCS)3, a major negative feedback regulator of STAT3-activating cytokines that negatively regulates Th17 cells. However, it is still largely unclear how TGF-β regulates Th17 cell development and which TGF-β signaling pathway is involved in Th17 cell development. In this report, we demonstrate that TGF-β inhibits IL-6- and IL-21-induced SOCS3 expression, thus enhancing as well as prolonging STAT3 activation in naive CD4⁺CD25^– T cells. TGF-β inhibits IL-6-induced SOCS3 promoter activity in T cells. Also, SOCS3 small interfering RNA knockdown partially compensates for the action of TGF-β on Th17 cell development. In mice with a dominant-negative form of TGF-β receptor II and impaired TGF-β signaling, IL-6-induced CD4⁺ T cell expression of SOCS3 is higher whereas STAT3 activation is lower compared with wild-type B6 CD4⁺ T cells. The addition of a TGF-β receptor I kinase inhibitor that blocks Smad-dependent TGF-β signaling greatly, but not completely, abrogates the effect of TGF-β on Th17 cell differentiation. Our data indicate that inhibition of SOCS3 and, thus, enhancement of STAT3 activation is at least one of the mechanisms of TGF-β promotion of Th17 cell development.

Address correspondence and reprint requests to Dr. Yingzi Cong, Shelby Building (SHEL) 605, Division of Gastroenterology and Hepatology, University of Alabama at Birmingham, 1825 University Boulevard, Birmingham, AL 35294-0007. E-mail address: ycong{at}uab.edu or Dr. Hongwei Qin, Department of Cell Biology, University of Alabama at Birmingham, 1918 University Boulevard, McCallum Building (MCLM) 392, Birmingham, AL 35294-0005. E-mail address: hqin{at}uab.edu.