期刊
JOURNAL OF IMMUNOLOGY
卷 183, 期 1, 页码 97-105出版社
AMER ASSOC IMMUNOLOGISTS
DOI: 10.4049/jimmunol.0801986
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资金
- National Institutes of Health [NS45290, P01 DK071176, DK60132, DK079918]
- National Multiple Sclerosis Society [RG-3892, PP-1475]
- Digestive Diseases Research Development Center [DK064400]
TGF-beta, 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-beta regulates Th17 cell development and which TGF-beta signaling pathway is involved in Th17 cell development. In this report, we demonstrate that TGF-beta inhibits IL-6- and IL-21-induced SOCS3 expression, thus enhancing as well as prolonging STAT3 activation in naive CD4(+)CD25(-) T cells. TGF-beta inhibits IL-6-induced SOCS3 promoter activity in T cells. Also, SOCS3 small interfering RNA knockdown partially compensates for the fiction of TGF-beta on Th17 cell development. In mice with a dominant-negative form of TGF-beta receptor II and impaired TGF-beta 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-beta receptor I kinase inhibitor that blocks Smad-dependent TGF-beta signaling greatly, but not completely, abrogates the effect of TGF-beta 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-beta promotion of Th17 cell development. The Journal of Immunology, 2009, 183: 97-105.
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