Abstract
The Toll-like receptor 3 (TLR3) and TLR4-signaling pathway that involves the adaptor protein TRIF activates type I interferon (IFN) and proinflammatory cytokine expression. Little is known about how TRIF pathway-dependent gene expression is regulated. SH2-containing protein tyrosine phosphatase 2 (SHP-2) is a widely expressed cytoplasmic tyrosine phosphatase. Here we demonstrate that SHP-2 negatively regulated TLR4- and TLR3-activated IFN-beta production. SHP-2 inhibited TLR3-activated but not TLR2-, TLR7-, and TLR9-activated proinflammatory cytokine IL-6 and TNF-alpha production. SHP-2 inhibited poly(I:C)-induced cytokine production by a phosphatase activity-independent mechanism. C-terminal domain of SHP-2 directly bound TANK binding kinase (TBK1) by interacting with the kinase domain of TBK1. SHP-2 deficiency increased TBK1-activated IFN-beta and TNF-alpha expression. TBK1 knockdown inhibited poly(I:C)-induced IL-6 production in SHP-2-deficient cells. SHP-2 also inhibited poly(I:C)-induced activation of MAP kinase pathways. These results demonstrate that SHP-2 specifically negatively regulate TRIF-mediated gene expression in TLR signaling, partially through inhibiting TBK1-activated signal transduction.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Adaptor Proteins, Vesicular Transport / immunology
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Adaptor Proteins, Vesicular Transport / metabolism*
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Animals
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Cells, Cultured
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Cytokines / biosynthesis*
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Cytokines / immunology
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Female
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Gene Expression
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Gene Expression Regulation / immunology
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Immunoblotting
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Interferon Type I / biosynthesis*
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Interferon Type I / immunology
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MAP Kinase Signaling System / immunology
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Macrophages / immunology
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Macrophages / metabolism
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Mice
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Mice, Inbred C57BL
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Protein Phosphatase 2
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Protein Serine-Threonine Kinases / immunology
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Protein Serine-Threonine Kinases / metabolism
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Protein Tyrosine Phosphatase, Non-Receptor Type 6 / immunology
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Protein Tyrosine Phosphatase, Non-Receptor Type 6 / metabolism*
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RNA, Small Interfering
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Signal Transduction / immunology*
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Toll-Like Receptors / immunology
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Toll-Like Receptors / metabolism
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Transfection
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Tumor Necrosis Factor-alpha / immunology
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Tumor Necrosis Factor-alpha / metabolism
Substances
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Adaptor Proteins, Vesicular Transport
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Cytokines
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Interferon Type I
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RNA, Small Interfering
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TICAM-1 protein, mouse
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Toll-Like Receptors
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Tumor Necrosis Factor-alpha
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Tbk1 protein, mouse
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Protein Serine-Threonine Kinases
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Protein Phosphatase 2
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Protein Tyrosine Phosphatase, Non-Receptor Type 6