Abstract
Interleukin 6 (IL-6) is a cytokine produced by immune and nonimmune cells and exhibits functional pleiotropy and redundancy. IL-6 plays an important role in the differentiation of several cell types. Here, we describe a novel function of IL-6: the negative regulation of CD4+ Th1 cell differentiation. While IL-6-directed CD4+ Th2 differentiation is mediated by IL-4, inhibition of Th1 differentiation by IL-6 is independent of IL-4. IL-6 upregulates suppressor of cytokine signaling 1 (SOCS1) expression in activated CD4+ T cells, thereby interfering with signal transducer and activator of transcription 1 (STAT1) phosphorylation induced by interferon gamma (IFNgamma). Inhibition of IFNgamma receptor-mediated signals by IL-6 prevents autoregulation of IFNgamma gene expression by IFNgamma during CD4+ T cell activation, thereby preventing Th1 differentiation. Thus, IL-6 promotes CD4+ Th2 differentiation and inhibits Th1 differentiation by two independent molecular mechanisms.
Publication types
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Animals
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Antigen-Presenting Cells / metabolism
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Carrier Proteins / metabolism*
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Cell Differentiation
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DNA-Binding Proteins / metabolism
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Gene Expression
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Interferon gamma Receptor
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Interferon-gamma / genetics
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Interferon-gamma / metabolism
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Interleukin-12 / metabolism
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Interleukin-4 / biosynthesis
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Interleukin-6 / metabolism*
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Interleukin-6 / pharmacology
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Mice
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Receptors, Interferon / metabolism
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Repressor Proteins*
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STAT1 Transcription Factor
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Signal Transduction*
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Suppressor of Cytokine Signaling 1 Protein
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Suppressor of Cytokine Signaling Proteins
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Th1 Cells / cytology*
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Th1 Cells / metabolism
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Trans-Activators / metabolism
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Up-Regulation
Substances
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Carrier Proteins
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DNA-Binding Proteins
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Interleukin-6
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Receptors, Interferon
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Repressor Proteins
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STAT1 Transcription Factor
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Socs1 protein, mouse
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Stat1 protein, mouse
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Suppressor of Cytokine Signaling 1 Protein
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Suppressor of Cytokine Signaling Proteins
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Trans-Activators
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Interleukin-12
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Interleukin-4
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Interferon-gamma