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rdf:type |
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lifeskim:mentions |
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pubmed:issue |
3
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pubmed:dateCreated |
2004-11-19
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pubmed:abstractText |
Myeloid differentiation protein-88 (MyD88) is a signal adaptor protein required for cytokine production following engagement of Toll-like receptors (TLRs) by their cognate ligands. Activation of both TLR-3 and TLR-4, however, can engage signaling events independent of MyD88 expression. The relative importance of these MyD88-dependent and -independent signaling pathways in the macrophage response to lipopolysaccharide (LPS) is unknown. Here we define these events using microarray expression profiling of LPS-stimulated macrophages taken from MyD88-null and wild-type mice. Of the 1,055 genes found to be LPS responsive, only 21.5% were dependent on MyD88 expression, with MyD88-independent genes constituting 74.7% of the genetic response. This MyD88-independent gene expression was predominantly transcriptionally regulated, as it was unaffected by cycloheximide blockade of new protein synthesis. A previously undescribed group of LPS-regulated genes (3.8%), whose induction or repression was significantly greater in the absence of MyD88, was also identified by these studies. The regulation of these genes suggested that MyD88 could serve as a molecular brake, constraining gene activity in a subset of LPS-responsive genes. The findings generated with LPS stimulation were recapitulated by exposure of macrophages to live Escherichia coli. These expression-profiling studies redefine the current dogma of TLR-4 signaling and establish that MyD88, although essential for some of the best-characterized macrophage responses to LPS, is not required for the regulation of the majority of genes engaged by macrophage exposure to endotoxin or live bacteria.
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pubmed:grant |
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pubmed:language |
eng
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pubmed:journal |
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pubmed:citationSubset |
IM
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pubmed:chemical |
http://linkedlifedata.com/resource/pubmed/chemical/Adaptor Proteins, Signal Transducing,
http://linkedlifedata.com/resource/pubmed/chemical/Antigens, Differentiation,
http://linkedlifedata.com/resource/pubmed/chemical/DNA-Binding Proteins,
http://linkedlifedata.com/resource/pubmed/chemical/Genetic Markers,
http://linkedlifedata.com/resource/pubmed/chemical/IRF3 protein, human,
http://linkedlifedata.com/resource/pubmed/chemical/Interferon Regulatory Factor-3,
http://linkedlifedata.com/resource/pubmed/chemical/Irf3 protein, mouse,
http://linkedlifedata.com/resource/pubmed/chemical/Lipopolysaccharides,
http://linkedlifedata.com/resource/pubmed/chemical/MYD88 protein, human,
http://linkedlifedata.com/resource/pubmed/chemical/Myd88 protein, mouse,
http://linkedlifedata.com/resource/pubmed/chemical/Myeloid Differentiation Factor 88,
http://linkedlifedata.com/resource/pubmed/chemical/NF-kappa B,
http://linkedlifedata.com/resource/pubmed/chemical/Proteins,
http://linkedlifedata.com/resource/pubmed/chemical/Receptors, Immunologic,
http://linkedlifedata.com/resource/pubmed/chemical/Tlr4 protein, mouse,
http://linkedlifedata.com/resource/pubmed/chemical/Toll-Like Receptor 4,
http://linkedlifedata.com/resource/pubmed/chemical/Transcription Factors,
http://linkedlifedata.com/resource/pubmed/chemical/vig1 protein, mouse
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pubmed:status |
MEDLINE
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pubmed:month |
Nov
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pubmed:issn |
1531-2267
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pubmed:author |
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pubmed:issnType |
Electronic
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pubmed:day |
17
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pubmed:volume |
19
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pubmed:owner |
NLM
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pubmed:authorsComplete |
Y
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pubmed:pagination |
319-30
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pubmed:dateRevised |
2007-11-14
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pubmed:meshHeading |
pubmed-meshheading:15367722-Adaptor Proteins, Signal Transducing,
pubmed-meshheading:15367722-Animals,
pubmed-meshheading:15367722-Antigens, Differentiation,
pubmed-meshheading:15367722-Cells, Cultured,
pubmed-meshheading:15367722-DNA-Binding Proteins,
pubmed-meshheading:15367722-Escherichia coli K12,
pubmed-meshheading:15367722-Gene Expression Profiling,
pubmed-meshheading:15367722-Gene Expression Regulation,
pubmed-meshheading:15367722-Genetic Markers,
pubmed-meshheading:15367722-Humans,
pubmed-meshheading:15367722-Inflammation,
pubmed-meshheading:15367722-Interferon Regulatory Factor-3,
pubmed-meshheading:15367722-Kidney,
pubmed-meshheading:15367722-Lipopolysaccharides,
pubmed-meshheading:15367722-Macrophage Activation,
pubmed-meshheading:15367722-Macrophages,
pubmed-meshheading:15367722-Mice,
pubmed-meshheading:15367722-Mice, Inbred C57BL,
pubmed-meshheading:15367722-Microarray Analysis,
pubmed-meshheading:15367722-Myeloid Differentiation Factor 88,
pubmed-meshheading:15367722-NF-kappa B,
pubmed-meshheading:15367722-Proteins,
pubmed-meshheading:15367722-Receptors, Immunologic,
pubmed-meshheading:15367722-Signal Transduction,
pubmed-meshheading:15367722-Toll-Like Receptor 4,
pubmed-meshheading:15367722-Transcription Factors,
pubmed-meshheading:15367722-Transfection
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pubmed:year |
2004
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pubmed:articleTitle |
The induction of macrophage gene expression by LPS predominantly utilizes Myd88-independent signaling cascades.
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pubmed:affiliation |
Lipid Metabolism Unit, Department of Molecular Biology, Massachusetts General Hospital, Boston 02114, USA.
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pubmed:publicationType |
Journal Article,
Research Support, U.S. Gov't, P.H.S.,
Research Support, Non-U.S. Gov't,
Research Support, N.I.H., Extramural
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