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.
Publication types
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Research Support, N.I.H., Intramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Cell Differentiation / immunology*
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Cells, Cultured
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Flow Cytometry
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Gene Expression
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Immunoblotting
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Interleukin-17 / biosynthesis
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Interleukin-23 / immunology
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Interleukin-23 / metabolism*
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Interleukin-6 / immunology
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Interleukin-6 / metabolism*
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Interleukins / immunology
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Interleukins / metabolism*
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Mice
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Mice, Mutant Strains
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Nuclear Receptor Subfamily 1, Group F, Member 3
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RNA, Messenger / analysis
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Receptors, Retinoic Acid / immunology
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Receptors, Retinoic Acid / metabolism
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Receptors, Thyroid Hormone / immunology
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Receptors, Thyroid Hormone / metabolism
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Reverse Transcriptase Polymerase Chain Reaction
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STAT3 Transcription Factor / immunology
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STAT3 Transcription Factor / metabolism
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Signal Transduction / immunology
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T-Lymphocyte Subsets / cytology*
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T-Lymphocyte Subsets / immunology
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T-Lymphocytes, Helper-Inducer / cytology*
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T-Lymphocytes, Helper-Inducer / immunology
Substances
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Interleukin-17
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Interleukin-23
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Interleukin-6
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Interleukins
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Nuclear Receptor Subfamily 1, Group F, Member 3
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RNA, Messenger
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Receptors, Retinoic Acid
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Receptors, Thyroid Hormone
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Rorc protein, mouse
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STAT3 Transcription Factor
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interleukin-21