Abstract
The recessive mutation 'Heedless' (hdl) was detected in third-generation N-ethyl-N-nitrosourea-mutated mice that showed defective responses to microbial inducers. Macrophages from Heedless homozygotes signaled by the MyD88-dependent pathway in response to rough lipopolysaccharide (LPS) and lipid A, but not in response to smooth LPS. In addition, the Heedless mutation prevented TRAM-TRIF-dependent signaling in response to all LPS chemotypes. Heedless also abolished macrophage responses to vesicular stomatitis virus and substantially inhibited responses to specific ligands for the Toll-like receptor 2 (TLR2)-TLR6 heterodimer. The Heedless phenotype was positionally ascribed to a premature stop codon in Cd14. Our data suggest that the TLR4-MD-2 complex distinguishes LPS chemotypes, but CD14 nullifies this distinction. Thus, the TLR4-MD-2 complex receptor can function in two separate modes: one in which full signaling occurs and one limited to MyD88-dependent signaling.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Adaptor Proteins, Signal Transducing
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Animals
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Antigens, Differentiation / genetics
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Antigens, Differentiation / metabolism*
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Antigens, Ly / chemistry
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Antigens, Ly / metabolism
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In Vitro Techniques
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Interferon Type I / biosynthesis
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Lipopolysaccharide Receptors / genetics
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Lipopolysaccharide Receptors / metabolism*
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Lipopolysaccharides / toxicity*
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Lymphocyte Antigen 96
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Macrophages, Peritoneal / drug effects
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Macrophages, Peritoneal / immunology
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Macrophages, Peritoneal / metabolism
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Mice
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Mice, Inbred C3H
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Mice, Inbred C57BL
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Mice, Knockout
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Mice, Mutant Strains
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Multiprotein Complexes
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Mutation
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Myeloid Differentiation Factor 88
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Receptors, Immunologic / chemistry
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Receptors, Immunologic / genetics
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Receptors, Immunologic / metabolism*
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Signal Transduction
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Toll-Like Receptor 4
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Vesicular stomatitis Indiana virus / pathogenicity
Substances
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Adaptor Proteins, Signal Transducing
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Antigens, Differentiation
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Antigens, Ly
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Interferon Type I
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Lipopolysaccharide Receptors
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Lipopolysaccharides
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Ly96 protein, mouse
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Lymphocyte Antigen 96
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Multiprotein Complexes
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Myd88 protein, mouse
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Myeloid Differentiation Factor 88
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Receptors, Immunologic
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Tlr4 protein, mouse
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Toll-Like Receptor 4