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IL-6 programs T(H)-17 cell differentiation by promoting sequential engagement of the IL-21 and IL-23 pathways.

Author(s): Liang Zhou, Ivaylo Ivanov, Rosanne Spolski, Roy Min, Kevin Shenderov, Takeshi Egawa, David E. Levy, Warren J. Leonard, Dan R. Littman

Publication date: 2007-08-31

Journal: Nature immunology

Keywords: Animals, Cell Differentiation, immunology, Cells, Cultured, Flow Cytometry, Gene Expression, Immunoblotting, Interleukin-17, biosynthesis, Interleukin-23, metabolism, Interleukin-6, Interleukins, Mice, Mice, Mutant Strains, Nuclear Receptor Subfamily 1, Group F, Member 3, RNA, Messenger, analysis, Receptors, Retinoic Acid, Receptors, Thyroid Hormone, Reverse Transcriptase Polymerase Chain Reaction, STAT3 Transcription Factor, Signal Transduction, T-Lymphocyte Subsets, cytology, T-Lymphocytes, Helper-Inducer

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Abstract

T helper cells that produce interleukin 17 (IL-17; 'T(H)-17 cells') are a distinct subset of proinflammatory cells whose in vivo function requires IL-23 but whose in vitro differentiation requires only IL-6 and transforming growth factor-beta (TGF-beta). We demonstrate here that IL-6 induced expression of IL-21 that amplified an autocrine loop to induce more IL-21 and IL-23 receptor in naive CD4(+) T cells. Both IL-21 and IL-23, along with TGF-beta, induced IL-17 expression independently of IL-6. The effects of IL-6 and IL-21 depended on STAT3, a transcription factor required for the differentiation of T(H)-17 cells in vivo. IL-21 and IL-23 induced the orphan nuclear receptor RORgammat, which in synergy with STAT3 promoted IL-17 expression. IL-6 therefore orchestrates a series of 'downstream' cytokine-dependent signaling pathways that, in concert with TGF-beta, amplify RORgammat-dependent differentiation of T(H)-17 cells.