Abstract
Recognition of pathogens by Toll-like receptors (TLRs) triggers innate immune responses through signaling pathways mediated by Toll-interleukin 1 receptor (TIR) domain-containing adaptors such as MyD88, TIRAP and TRIF. MyD88 is a common adaptor that is essential for proinflammatory cytokine production, whereas TRIF mediates the MyD88-independent pathway from TLR3 and TLR4. Here we have identified a fourth TIR domain-containing adaptor, TRIF-related adaptor molecule (TRAM), and analyzed its physiological function by gene targeting. TRAM-deficient mice showed defects in cytokine production in response to the TLR4 ligand, but not to other TLR ligands. TLR4- but not TLR3-mediated MyD88-independent interferon-beta production and activation of signaling cascades were abolished in TRAM-deficient cells. Thus, TRAM provides specificity for the MyD88-independent component of TLR4 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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Animals
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Antigens, Differentiation / metabolism
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B-Lymphocytes / physiology
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Cytokines / biosynthesis
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Membrane Glycoproteins / deficiency
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Membrane Glycoproteins / genetics*
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Membrane Glycoproteins / metabolism*
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Mice
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Molecular Sequence Data
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Myeloid Differentiation Factor 88
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Receptors, Cell Surface / metabolism*
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Receptors, Immunologic / metabolism
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Receptors, Interleukin-1 / metabolism
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Signal Transduction / physiology*
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Toll-Like Receptor 3
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Toll-Like Receptor 4
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Toll-Like Receptors
Substances
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Adaptor Proteins, Signal Transducing
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Antigens, Differentiation
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Cytokines
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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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Receptors, Cell Surface
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Receptors, Immunologic
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Receptors, Interleukin-1
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Toll-Like Receptor 3
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Toll-Like Receptor 4
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Toll-Like Receptors
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translocating chain-associating membrane protein (TRAM)