Source:http://linkedlifedata.com/resource/pubmed/id/17337443
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| Predicate | Object |
|---|---|
| rdf:type | |
| lifeskim:mentions | |
| pubmed:issue |
18
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| pubmed:dateCreated |
2007-4-30
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| pubmed:abstractText |
IRAK-4 is an essential component of the signal transduction complex downstream of the IL-1- and Toll-like receptors. Although regarded as the first kinase in the signaling cascade, the role of IRAK-4 kinase activity versus its scaffold function is still controversial. To investigate the role of IRAK-4 kinase function in vivo, "knock-in" mice were generated by replacing the wild type IRAK-4 gene with a mutant gene encoding kinase-deficient IRAK-4 protein (IRAK-4 KD). IRAK-4 kinase was rendered inactive by mutating the conserved lysine residues in the ATP pocket essential for coordinating ATP. Analyses of embryonic fibroblasts and macrophages obtained from IRAK-4 KD mice demonstrate lack of cellular responsiveness to stimulation with IL-1beta or a Toll-like receptor 7 (TLR7) agonist. IRAK-4 kinase deficiency prevents the recruitment of IRAK-1 to the IL-1 receptor complex and its subsequent phosphorylation and degradation. IRAK-4 KD cells are severely impaired in NFkappaB, JNK, and p38 activation in response to IL-1beta or TLR7 ligand. As a consequence, IL-1 receptor/TLR7-mediated production of cytokines and chemokines is largely absent in these cells. Additionally, microarray analysis identified IL-1beta response genes and revealed that the induction of IL-1beta-responsive mRNAs is largely ablated in IRAK-4 KD cells. In summary, our results suggest that IRAK-4 kinase activity plays a critical role in IL-1 receptor (IL-1R)/TLR7-mediated induction of inflammatory responses.
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| pubmed:language |
eng
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| pubmed:journal | |
| pubmed:citationSubset |
IM
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| pubmed:chemical |
http://linkedlifedata.com/resource/pubmed/chemical/Interleukin-1 Receptor-Associated...,
http://linkedlifedata.com/resource/pubmed/chemical/Irak4 protein, mouse,
http://linkedlifedata.com/resource/pubmed/chemical/Membrane Glycoproteins,
http://linkedlifedata.com/resource/pubmed/chemical/Multiprotein Complexes,
http://linkedlifedata.com/resource/pubmed/chemical/RNA, Messenger,
http://linkedlifedata.com/resource/pubmed/chemical/Receptors, Interleukin-1,
http://linkedlifedata.com/resource/pubmed/chemical/Tlr7 protein, mouse,
http://linkedlifedata.com/resource/pubmed/chemical/Toll-Like Receptor 7
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| pubmed:status |
MEDLINE
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| pubmed:month |
May
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| pubmed:issn |
0021-9258
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| pubmed:author | |
| pubmed:issnType |
Print
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| pubmed:day |
4
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| pubmed:volume |
282
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| pubmed:owner |
NLM
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| pubmed:authorsComplete |
Y
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| pubmed:pagination |
13552-60
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| pubmed:dateRevised |
2009-11-19
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| pubmed:meshHeading |
pubmed-meshheading:17337443-Animals,
pubmed-meshheading:17337443-Cell Line,
pubmed-meshheading:17337443-Embryo, Mammalian,
pubmed-meshheading:17337443-Fibroblasts,
pubmed-meshheading:17337443-Inflammation,
pubmed-meshheading:17337443-Interleukin-1 Receptor-Associated Kinases,
pubmed-meshheading:17337443-Macrophages,
pubmed-meshheading:17337443-Membrane Glycoproteins,
pubmed-meshheading:17337443-Mice,
pubmed-meshheading:17337443-Mice, Inbred BALB C,
pubmed-meshheading:17337443-Mice, Knockout,
pubmed-meshheading:17337443-Multiprotein Complexes,
pubmed-meshheading:17337443-Mutation,
pubmed-meshheading:17337443-Phosphorylation,
pubmed-meshheading:17337443-Protein Processing, Post-Translational,
pubmed-meshheading:17337443-RNA, Messenger,
pubmed-meshheading:17337443-Receptors, Interleukin-1,
pubmed-meshheading:17337443-Signal Transduction,
pubmed-meshheading:17337443-Toll-Like Receptor 7
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| pubmed:year |
2007
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| pubmed:articleTitle |
IRAK-4 kinase activity is required for interleukin-1 (IL-1) receptor- and toll-like receptor 7-mediated signaling and gene expression.
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| pubmed:affiliation |
Novartis Institutes for BioMedical Research, CH-4002 Basel, Switzerland.
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| pubmed:publicationType |
Journal Article
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