C4b-binding protein negatively regulates TLR4/MD-2 response but not TLR3 response

FEBS Lett. 2017 Jun;591(12):1732-1741. doi: 10.1002/1873-3468.12693. Epub 2017 Jun 12.

Abstract

Recently, we reported a novel function for C4b-binding protein (C4BP) in inhibiting the toll-like receptor (TLR)1/2 response by interacting with TLR2. TLRs share a common structure; hence, we examined the effect of C4BP on activation of other TLRs-TLR4 and TLR3. The results of immunoprecipitation assays suggest that C4BP interacts with TLR4/MD-2 but not TLR3. C4BP inhibits TLR4/MD-2-mediated, but not TLR3-mediated, proinflammatory cytokine production and nuclear factor (NF)-κB signaling. C4BP-deficient mice show increased interleukin (IL)-6 production in response to the TLR4/MD-2 ligand. A competition assay revealed that C4BP prevents an interaction between TLR4/MD-2 and its ligand. These findings indicate that C4BP binds to cell surface TLRs and inhibits the TLR-TLR ligand interaction, thereby inhibiting TLR activation.

Keywords: C4b-binding protein; lipopolysaccharide; toll-like receptor.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cytokines / agonists
  • Cytokines / antagonists & inhibitors
  • Cytokines / metabolism
  • Down-Regulation* / drug effects
  • Female
  • HEK293 Cells
  • Histocompatibility Antigens / chemistry
  • Histocompatibility Antigens / genetics
  • Histocompatibility Antigens / metabolism*
  • Humans
  • Ligands
  • Lipid A / toxicity
  • Lipopolysaccharides / toxicity
  • Lymphocyte Antigen 96 / agonists
  • Lymphocyte Antigen 96 / antagonists & inhibitors*
  • Lymphocyte Antigen 96 / genetics
  • Lymphocyte Antigen 96 / metabolism
  • Macrophage Activation* / drug effects
  • Macrophages / drug effects
  • Macrophages / immunology
  • Macrophages / metabolism*
  • Mice
  • Mice, Knockout
  • NF-kappa B / agonists
  • NF-kappa B / antagonists & inhibitors
  • NF-kappa B / metabolism
  • RAW 264.7 Cells
  • Recombinant Fusion Proteins / chemistry
  • Recombinant Fusion Proteins / metabolism
  • Recombinant Proteins / chemistry
  • Recombinant Proteins / metabolism
  • Signal Transduction* / drug effects
  • Toll-Like Receptor 3 / chemistry
  • Toll-Like Receptor 3 / genetics
  • Toll-Like Receptor 3 / metabolism
  • Toll-Like Receptor 4 / agonists
  • Toll-Like Receptor 4 / antagonists & inhibitors*
  • Toll-Like Receptor 4 / genetics
  • Toll-Like Receptor 4 / metabolism

Substances

  • C4bp protein, mouse
  • Cytokines
  • Histocompatibility Antigens
  • Ligands
  • Lipid A
  • Lipopolysaccharides
  • Ly96 protein, mouse
  • Lymphocyte Antigen 96
  • NF-kappa B
  • Recombinant Fusion Proteins
  • Recombinant Proteins
  • TLR3 protein, mouse
  • Tlr4 protein, mouse
  • Toll-Like Receptor 3
  • Toll-Like Receptor 4
  • lipopolysaccharide, E coli O55-B5