SIGIRR, a Negative Regulator of Toll-like Receptor-Interleukin 1 Receptor Signaling

Nat Immunol. 2003 Sep;4(9):920-7. doi: 10.1038/ni968. Epub 2003 Aug 17.

Abstract

The Toll-like receptor-interleukin 1 receptor signaling (TLR-IL-1R) receptor superfamily is important in differentially recognizing pathogen products and eliciting appropriate immune responses. These receptors alter gene expression, mainly through the activation of nuclear factor-kappaB and activating protein 1. SIGIRR (single immunoglobulin IL-1R-related molecule), a member of this family that does not activate these factors, instead negatively modulates immune responses. Inflammation is enhanced in SIGIRR-deficient mice, as shown by their enhanced chemokine induction after IL-1 injection and reduced threshold for lethal endotoxin challenge. Cells from SIGIRR-deficient mice showed enhanced activation in response to either IL-1 or certain Toll ligands. Finally, biochemical analysis indicated that SIGIRR binds to the TLR-IL-1R signaling components in a ligand-dependent way. Our data show that SIGIRR functions as a biologically important modulator of TLR-IL-1R signaling.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Chemokines / immunology
  • Chemokines / metabolism
  • Gene Expression Regulation
  • Humans
  • Immunoblotting
  • Interleukin-1 / immunology
  • Interleukin-18 / immunology
  • Jurkat Cells
  • Lipopolysaccharides / immunology
  • Membrane Glycoproteins / antagonists & inhibitors
  • Membrane Glycoproteins / immunology*
  • Mice
  • Mice, Inbred BALB C
  • Mice, Inbred C57BL
  • Mice, Knockout
  • NF-kappa B / immunology
  • RNA / chemistry
  • RNA / genetics
  • Receptors, Cell Surface / antagonists & inhibitors
  • Receptors, Cell Surface / immunology*
  • Receptors, Interleukin-1 / immunology*
  • Signal Transduction / immunology
  • Toll-Like Receptors
  • Transcription Factor AP-1 / immunology

Substances

  • Chemokines
  • Interleukin-1
  • Interleukin-18
  • Lipopolysaccharides
  • Membrane Glycoproteins
  • NF-kappa B
  • Receptors, Cell Surface
  • Receptors, Interleukin-1
  • Toll-Like Receptors
  • Transcription Factor AP-1
  • RNA