ST2 is an inhibitor of interleukin 1 receptor and Toll-like receptor 4 signaling and maintains endotoxin tolerance

Nat Immunol. 2004 Apr;5(4):373-9. doi: 10.1038/ni1050. Epub 2004 Mar 7.

Abstract

The Toll-interleukin 1 receptor (TIR) superfamily, defined by the presence of an intracellular TIR domain, initiates innate immunity through activation of the transcription factor NF-kappa B, leading to the production of proinflammatory cytokines. ST2 is a member of the TIR family that does not activate NF-kappa B and has been suggested as an important effector molecule of T helper type 2 (T(H)2) responses. We show here that the membrane-bound form of ST2 negatively regulated type I interleukin 1 receptor (IL-1RI) and Toll-like receptor 4 (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, these results provide a molecular explanation for the function of ST2 in T(H)2 responses, as inhibition of TLRs promotes 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

MeSH terms

  • Adaptor Proteins, Signal Transducing
  • Animals
  • Antigens, Differentiation
  • Cytokines / metabolism
  • Endotoxins / metabolism*
  • Inflammation / metabolism
  • Interleukin-1 Receptor-Like 1 Protein
  • Macrophages / metabolism
  • Membrane Glycoproteins / metabolism*
  • Membrane Proteins / deficiency
  • Membrane Proteins / metabolism*
  • Membrane Transport Proteins*
  • Mice
  • Myelin Proteins*
  • Myelin and Lymphocyte-Associated Proteolipid Proteins
  • Myeloid Differentiation Factor 88
  • Proteolipids / antagonists & inhibitors
  • Receptors, Cell Surface / metabolism*
  • Receptors, Immunologic / antagonists & inhibitors
  • Receptors, Interleukin
  • Receptors, Interleukin-1 / metabolism*
  • Signal Transduction / physiology
  • 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 Receptor-Like 1 Protein
  • 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