Abstract
Dysregulated cytokine expression and signaling are major contributors to a number of autoimmune diseases. Interleukin-17A (IL-17A) and IL-6 are important in many disorders characterized by immune self-recognition, and IL-6 is known to induce the differentiation of T helper 17 (Th17) cells. Here we described an IL-17A-triggered positive-feedback loop of IL-6 signaling, which involved the activation of the transcription factors nuclear factor (NF)-kappaB and signal transducer and activator of transcription 3 (STAT3) in fibroblasts. Importantly, enhancement of this loop caused by disruption of suppressor of cytokine signaling 3 (SOCS3)-dependent negative regulation of the IL-6 signal transducer gp130 contributed to the development of arthritis. Because this mechanism also enhanced experimental autoimmune encephalomyelitis (EAE) in wild-type mice, it may be a general etiologic process underlying other Th17 cell-mediated autoimmune diseases.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Arthritis / immunology
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Arthritis / metabolism
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Autoimmunity*
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Cytokine Receptor gp130 / immunology
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Cytokine Receptor gp130 / metabolism
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Encephalomyelitis, Autoimmune, Experimental / immunology
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Encephalomyelitis, Autoimmune, Experimental / metabolism
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Feedback, Physiological
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Fibroblasts / immunology*
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Fibroblasts / metabolism
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Interleukin-17 / immunology
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Interleukin-17 / metabolism
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Interleukin-6 / immunology
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Interleukin-6 / metabolism*
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Mice
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Mice, Inbred C57BL
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Mice, Mutant Strains
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NF-kappa B / metabolism
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STAT3 Transcription Factor / metabolism*
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Signal Transduction
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Suppressor of Cytokine Signaling 3 Protein
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Suppressor of Cytokine Signaling Proteins / immunology
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Suppressor of Cytokine Signaling Proteins / metabolism*
Substances
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Interleukin-17
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Interleukin-6
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NF-kappa B
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STAT3 Transcription Factor
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Socs3 protein, mouse
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Stat3 protein, mouse
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Suppressor of Cytokine Signaling 3 Protein
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Suppressor of Cytokine Signaling Proteins
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Cytokine Receptor gp130