A novel negative regulator for IL-1 receptor and Toll-like receptor 4

Immunol Lett. 2005 Jan 15;96(1):27-31. doi: 10.1016/j.imlet.2004.07.008.

Abstract

The Toll-IL-1 receptor (TIR) superfamily, defined by the presence of an intracellular TIR domain, initiates innate immunity via NF-kappaB activation, leading to production of proinflammatory cytokines. ST2 is a member of the TIR family that does not activate NF-kappaB and has been suggested as an important effector molecule of type 2 T helper cell responses. We have recently demonstrated that the membrane bound form of ST2 (ST2L) negatively regulated IL-1RI and TLR4 but not TLR3 signaling by sequestrating the adaptors MyD88 and Mal. In contrast to wild-type mice, ST2 deficient mice failed to develop endotoxin tolerance. Thus, ST2 suppresses IL-1R and TLR4 signaling via MyD88- and Mal-dependent pathways and modulates innate immunity. The results provide a molecular explanation for the role of ST2 in T(H)2 responses since inhibition of TLRs will promote a T(H)2 response and also identify ST2 as a key regulator of endotoxin tolerance.

Publication types

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

MeSH terms

  • Adaptor Proteins, Signal Transducing
  • Animals
  • Antigens, Differentiation / metabolism
  • Cytokines / metabolism
  • Down-Regulation / physiology*
  • Endotoxins / metabolism
  • Interleukin-1 / metabolism
  • Interleukin-1 Receptor-Like 1 Protein
  • Lipopolysaccharides / immunology
  • Membrane Glycoproteins / metabolism*
  • Membrane Proteins / metabolism*
  • Membrane Transport Proteins / metabolism
  • Mice
  • Myelin Proteins / metabolism
  • Myelin and Lymphocyte-Associated Proteolipid Proteins
  • Myeloid Differentiation Factor 88
  • Proteolipids / metabolism
  • Receptors, Cell Surface / metabolism*
  • Receptors, Immunologic / metabolism
  • Receptors, Interleukin
  • Receptors, Interleukin-1 / metabolism*
  • Toll-Like Receptor 3
  • Toll-Like Receptor 4
  • Toll-Like Receptors

Substances

  • Adaptor Proteins, Signal Transducing
  • Antigens, Differentiation
  • Cytokines
  • Endotoxins
  • Il1rl1 protein, mouse
  • Interleukin-1
  • Interleukin-1 Receptor-Like 1 Protein
  • Lipopolysaccharides
  • Mal protein, mouse
  • Membrane Glycoproteins
  • Membrane Proteins
  • Membrane Transport Proteins
  • Myd88 protein, mouse
  • Myelin Proteins
  • Myelin and Lymphocyte-Associated Proteolipid Proteins
  • Myeloid Differentiation Factor 88
  • Proteolipids
  • Receptors, Cell Surface
  • Receptors, Immunologic
  • Receptors, Interleukin
  • Receptors, Interleukin-1
  • Toll-Like Receptor 3
  • Toll-Like Receptor 4
  • Toll-Like Receptors