Abstract
Although production of cytokines by TLR is essential for viral and bacterial clearance, overproduction can be detrimental, thus controlling these responses is essential. CD33-related sialic acid binding Ig-like lectin receptors (Siglecs) have been implicated in the control of leukocyte responses. In this study, we report that murine Siglec-E is induced by TLRs in a MyD88-specific manner, is tyrosine phosphorylated following LPS stimulation, and negatively regulates TLR responses. Specifically, we demonstrate the Siglec-E expression inhibits TLR-induced NF-kappaB and more importantly, the induction of the antiviral cytokines IFN-beta and RANTES. Siglec-E mediates its inhibitory effects on TIR domain containing adaptor inducing IFN-beta (TRIF)-dependent cytokine production via recruitment of the tyrosine [corrected] phosphatase SHP2 and subsequent inhibition of TBK1 activity as evidenced by enhanced TBK1 phosphorylation in cells following knockdown of Siglec-E expression. Taken together, our results demonstrate a novel role for Siglec-E in controlling the antiviral response to TLRs and thus helping to maintain a healthy cytokine balance following infection.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Adaptor Proteins, Vesicular Transport / antagonists & inhibitors
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Adaptor Proteins, Vesicular Transport / genetics
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Adaptor Proteins, Vesicular Transport / physiology
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Animals
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Antigens, CD / biosynthesis*
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Antigens, CD / metabolism
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Antigens, CD / physiology
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Antigens, Differentiation, B-Lymphocyte / biosynthesis*
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Antigens, Differentiation, B-Lymphocyte / metabolism
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Antigens, Differentiation, B-Lymphocyte / physiology
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Cell Line
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Cell Line, Transformed
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Cytokines / antagonists & inhibitors*
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Cytokines / biosynthesis*
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Cytokines / genetics
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Down-Regulation / genetics
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Down-Regulation / immunology*
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Humans
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Lipopolysaccharides / pharmacology*
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Mice
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Mice, Inbred C57BL
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Mice, Knockout
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Myeloid Differentiation Factor 88 / physiology
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NF-kappa B / antagonists & inhibitors
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NF-kappa B / metabolism
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Phosphorylation / immunology
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Protein Tyrosine Phosphatase, Non-Receptor Type 11 / metabolism
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Protein Tyrosine Phosphatase, Non-Receptor Type 11 / physiology
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Signal Transduction / genetics
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Signal Transduction / immunology
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Toll-Like Receptors / antagonists & inhibitors*
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Toll-Like Receptors / physiology*
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Up-Regulation / immunology*
Substances
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Adaptor Proteins, Vesicular Transport
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Antigens, CD
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Antigens, Differentiation, B-Lymphocyte
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Cytokines
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Lipopolysaccharides
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Myd88 protein, mouse
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Myeloid Differentiation Factor 88
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NF-kappa B
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Siglece protein, mouse
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TICAM-1 protein, mouse
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Toll-Like Receptors
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Protein Tyrosine Phosphatase, Non-Receptor Type 11
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Ptpn11 protein, mouse