Cutting Edge: TNFR-associated Factor (TRAF) 6 Is Essential for MyD88-dependent Pathway but Not toll/IL-1 Receptor Domain-Containing Adaptor-Inducing IFN-beta (TRIF)-dependent Pathway in TLR Signaling

J Immunol. 2004 Sep 1;173(5):2913-7. doi: 10.4049/jimmunol.173.5.2913.

Abstract

Signaling pathways from TLRs are mediated by the Toll/IL-1R (TIR) domain-containing adaptor molecules. TNF receptor-associated factor (TRAF) 6 is thought to activate NF-kappaB and MAPKs downstream of these TIR domain-containing proteins to induce production of inflammatory cytokines. However, the precise role of TRAF6 in signaling from individual TLRs has not been appropriately addressed. We analyzed macrophages from TRAF6-deficient mice and made the following observations. In the absence of TRAF6, 1) ligands for TLR2, TLR5, TLR7, and TLR9 failed to induce activation of NF-kappaB and MAPKs or production of inflammatory cytokines; 2) TLR4 ligand-induced cytokine production was remarkably reduced and activation of NF-kappaB and MAPKs was observed, albeit with delayed kinetics; and 3) in contrast with previously reported findings, TLR3 signaling was not affected. These results indicate that TRAF6 is essential for MyD88-dependent signaling but is not required for TIR domain-containing adaptor-inducing IFN-beta (TRIF)-dependent signaling.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptor Proteins, Signal Transducing
  • Adaptor Proteins, Vesicular Transport / genetics
  • Adaptor Proteins, Vesicular Transport / metabolism*
  • Animals
  • Antigens, Differentiation / metabolism*
  • Humans
  • Macrophages / metabolism
  • Membrane Glycoproteins / genetics
  • Membrane Glycoproteins / metabolism*
  • Mice
  • Myeloid Differentiation Factor 88
  • Proteins / genetics
  • Proteins / metabolism*
  • Receptors, Cell Surface / metabolism*
  • Receptors, Immunologic / metabolism*
  • Receptors, Interleukin-1 / genetics
  • Receptors, Interleukin-1 / metabolism
  • Signal Transduction / physiology*
  • TNF Receptor-Associated Factor 6
  • Toll-Like Receptor 2
  • Toll-Like Receptor 3
  • Toll-Like Receptor 4
  • Toll-Like Receptor 5
  • Toll-Like Receptor 7
  • Toll-Like Receptor 9
  • Toll-Like Receptors

Substances

  • Adaptor Proteins, Signal Transducing
  • Adaptor Proteins, Vesicular Transport
  • Antigens, Differentiation
  • MYD88 protein, human
  • Membrane Glycoproteins
  • Myd88 protein, mouse
  • Myeloid Differentiation Factor 88
  • Proteins
  • Receptors, Cell Surface
  • Receptors, Immunologic
  • Receptors, Interleukin-1
  • TICAM-1 protein, mouse
  • TIRAP protein, human
  • TIRAP protein, mouse
  • TLR2 protein, human
  • TLR3 protein, human
  • TLR4 protein, human
  • TLR5 protein, human
  • TLR7 protein, human
  • TLR9 protein, human
  • TNF Receptor-Associated Factor 6
  • Toll-Like Receptor 2
  • Toll-Like Receptor 3
  • Toll-Like Receptor 4
  • Toll-Like Receptor 5
  • Toll-Like Receptor 7
  • Toll-Like Receptor 9
  • Toll-Like Receptors