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
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Research Support, Non-U.S. Gov't
MeSH terms
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Adaptor Proteins, Signal Transducing
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Adaptor Proteins, Vesicular Transport / genetics
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Adaptor Proteins, Vesicular Transport / metabolism*
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Animals
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Antigens, Differentiation / metabolism*
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Humans
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Macrophages / metabolism
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Membrane Glycoproteins / genetics
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Membrane Glycoproteins / metabolism*
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Mice
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Myeloid Differentiation Factor 88
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Proteins / genetics
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Proteins / metabolism*
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Receptors, Cell Surface / metabolism*
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Receptors, Immunologic / metabolism*
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Receptors, Interleukin-1 / genetics
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Receptors, Interleukin-1 / metabolism
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Signal Transduction / physiology*
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TNF Receptor-Associated Factor 6
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Toll-Like Receptor 2
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Toll-Like Receptor 3
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Toll-Like Receptor 4
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Toll-Like Receptor 5
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Toll-Like Receptor 7
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Toll-Like Receptor 9
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Toll-Like Receptors
Substances
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Adaptor Proteins, Signal Transducing
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Adaptor Proteins, Vesicular Transport
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Antigens, Differentiation
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MYD88 protein, human
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Membrane Glycoproteins
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Myd88 protein, mouse
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Myeloid Differentiation Factor 88
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Proteins
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Receptors, Cell Surface
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Receptors, Immunologic
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Receptors, Interleukin-1
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TICAM-1 protein, mouse
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TIRAP protein, human
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TIRAP protein, mouse
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TLR2 protein, human
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TLR3 protein, human
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TLR4 protein, human
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TLR5 protein, human
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TLR7 protein, human
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TLR9 protein, human
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TNF Receptor-Associated Factor 6
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Toll-Like Receptor 2
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Toll-Like Receptor 3
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Toll-Like Receptor 4
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Toll-Like Receptor 5
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Toll-Like Receptor 7
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Toll-Like Receptor 9
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Toll-Like Receptors