Abstract
Whereas interleukin-6 (IL-6) is a proinflammatory cytokine, IL-10 is an anti-inflammatory cytokine. Although signal transducer and activator of transcription 3 (STAT3) is essential for the function of both IL-6 and IL-10, it is unclear how these two cytokines have such opposing functions. Here we show that suppressor of cytokine signaling 3 (SOCS3) is a key regulator of the divergent action of these two cytokines. In macrophages lacking the Socs3 gene or carrying a mutation of the SOCS3-binding site in gp130, the lipopolysaccharide-induced production of tumor necrosis factor (TNF) and IL-12 is suppressed by both IL-10 and IL-6. SOCS3 specifically prevents activation of STAT3 by IL-6 but not IL-10. Taken together, these data indicate that SOCS3 selectively blocks signaling by IL-6, thereby preventing its ability to inhibit LPS signaling.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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DNA-Binding Proteins / immunology
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Female
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Immunoblotting
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Interleukin-10 / immunology
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Interleukin-6 / antagonists & inhibitors
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Interleukin-6 / immunology*
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Lipopolysaccharides / immunology
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Macrophages, Peritoneal / immunology
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Macrophages, Peritoneal / metabolism
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Male
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Membrane Glycoproteins / immunology
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Mice
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Mice, Inbred C57BL
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Mice, Knockout
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Proteins / immunology*
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Repressor Proteins*
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STAT3 Transcription Factor
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Signal Transduction / immunology
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Suppressor of Cytokine Signaling 3 Protein
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Suppressor of Cytokine Signaling Proteins
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Trans-Activators / immunology
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Transcription Factors*
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Tumor Necrosis Factor-alpha / metabolism
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src Homology Domains / immunology
Substances
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DNA-Binding Proteins
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Interleukin-6
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Lipopolysaccharides
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Membrane Glycoproteins
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Proteins
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Repressor Proteins
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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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Trans-Activators
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Transcription Factors
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Tumor Necrosis Factor-alpha
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Interleukin-10