Siglec-E is up-regulated and phosphorylated following lipopolysaccharide stimulation in order to limit TLR-driven cytokine production

J Immunol. 2009 Dec 15;183(12):7703-9. doi: 10.4049/jimmunol.0902780.

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

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptor Proteins, Vesicular Transport / antagonists & inhibitors
  • Adaptor Proteins, Vesicular Transport / genetics
  • Adaptor Proteins, Vesicular Transport / physiology
  • Animals
  • Antigens, CD / biosynthesis*
  • Antigens, CD / metabolism
  • Antigens, CD / physiology
  • Antigens, Differentiation, B-Lymphocyte / biosynthesis*
  • Antigens, Differentiation, B-Lymphocyte / metabolism
  • Antigens, Differentiation, B-Lymphocyte / physiology
  • Cell Line
  • Cell Line, Transformed
  • Cytokines / antagonists & inhibitors*
  • Cytokines / biosynthesis*
  • Cytokines / genetics
  • Down-Regulation / genetics
  • Down-Regulation / immunology*
  • Humans
  • Lipopolysaccharides / pharmacology*
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Myeloid Differentiation Factor 88 / physiology
  • NF-kappa B / antagonists & inhibitors
  • NF-kappa B / metabolism
  • Phosphorylation / immunology
  • Protein Tyrosine Phosphatase, Non-Receptor Type 11 / metabolism
  • Protein Tyrosine Phosphatase, Non-Receptor Type 11 / physiology
  • Signal Transduction / genetics
  • Signal Transduction / immunology
  • Toll-Like Receptors / antagonists & inhibitors*
  • Toll-Like Receptors / physiology*
  • Up-Regulation / immunology*

Substances

  • Adaptor Proteins, Vesicular Transport
  • Antigens, CD
  • Antigens, Differentiation, B-Lymphocyte
  • Cytokines
  • Lipopolysaccharides
  • Myd88 protein, mouse
  • Myeloid Differentiation Factor 88
  • NF-kappa B
  • Siglece protein, mouse
  • TICAM-1 protein, mouse
  • Toll-Like Receptors
  • Protein Tyrosine Phosphatase, Non-Receptor Type 11
  • Ptpn11 protein, mouse