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rdf:type |
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lifeskim:mentions |
umls-concept:C0026809,
umls-concept:C0036974,
umls-concept:C0682972,
umls-concept:C0851285,
umls-concept:C1367690,
umls-concept:C1426330,
umls-concept:C1428424,
umls-concept:C1549649,
umls-concept:C1704259,
umls-concept:C1705987,
umls-concept:C2349209
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pubmed:issue |
3
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pubmed:dateCreated |
2010-12-30
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pubmed:abstractText |
G-protein-coupled receptor kinase 2 (GRK2) is a member of a kinase family originally discovered for its role in the phosphorylation and desensitization of G-protein-coupled receptors. It is expressed in high levels in myeloid cells and its levels are altered in many inflammatory disorders including sepsis. To address the physiological role of myeloid cell-specific GRK2 in inflammation, we generated mice bearing GRK2 deletion in myeloid cells (GRK2?mye). GRK2?mye mice exhibited exaggerated inflammatory cytokine/chemokine production, and organ injury in response to lipopolysaccharide (LPS, a TLR4 ligand) when compared to wild-type littermates (GRK2fl/fl). Consistent with this, peritoneal macrophages from GRK2?mye mice showed enhanced inflammatory cytokine levels when stimulated with LPS. Our results further identify TLR4-induced NF-?B1p105-ERK pathway to be selectively regulated by GRK2. LPS-induced activation of NF-?B1p105-MEK-ERK pathway is significantly enhanced in the GRK2?mye macrophages compared to GRK2fl/fl cells and importantly, inhibition of the p105 and ERK pathways in the GRK2?mye macrophages, limits the enhanced production of LPS-induced cytokines/chemokines. Taken together, our studies reveal previously undescribed negative regulatory role for GRK2 in TLR4-induced p105-ERK pathway as well as in the consequent inflammatory cytokine/chemokine production and endotoxemia in mice.
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pubmed:grant |
http://linkedlifedata.com/resource/pubmed/grant/AR055726,
http://linkedlifedata.com/resource/pubmed/grant/AR056680,
http://linkedlifedata.com/resource/pubmed/grant/HL095637,
http://linkedlifedata.com/resource/pubmed/grant/R01 AR056680-01A2,
http://linkedlifedata.com/resource/pubmed/grant/R01 AR056680-02,
http://linkedlifedata.com/resource/pubmed/grant/R01 AR056680-03,
http://linkedlifedata.com/resource/pubmed/grant/R01 HL087871-06,
http://linkedlifedata.com/resource/pubmed/grant/R01 HL095637-01,
http://linkedlifedata.com/resource/pubmed/grant/R01 HL095637-02,
http://linkedlifedata.com/resource/pubmed/grant/R01 HL095637-03,
http://linkedlifedata.com/resource/pubmed/grant/R21 AR055726-01A1,
http://linkedlifedata.com/resource/pubmed/grant/R21 AR055726-02
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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/Ccl3 protein, mouse,
http://linkedlifedata.com/resource/pubmed/chemical/Chemokine CCL3,
http://linkedlifedata.com/resource/pubmed/chemical/Extracellular Signal-Regulated MAP...,
http://linkedlifedata.com/resource/pubmed/chemical/G-Protein-Coupled Receptor Kinase 2,
http://linkedlifedata.com/resource/pubmed/chemical/Interleukin-10,
http://linkedlifedata.com/resource/pubmed/chemical/Interleukin-12 Subunit p40,
http://linkedlifedata.com/resource/pubmed/chemical/Lipopolysaccharides,
http://linkedlifedata.com/resource/pubmed/chemical/MAP Kinase Kinase Kinases,
http://linkedlifedata.com/resource/pubmed/chemical/Mitogen-Activated Protein Kinase...,
http://linkedlifedata.com/resource/pubmed/chemical/NF-kappa B p50 Subunit,
http://linkedlifedata.com/resource/pubmed/chemical/Nfkb1 protein, mouse
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pubmed:status |
MEDLINE
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pubmed:month |
Mar
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pubmed:issn |
1097-4652
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pubmed:author |
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pubmed:copyrightInfo |
Copyright © 2010 Wiley-Liss, Inc.
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pubmed:issnType |
Electronic
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pubmed:volume |
226
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pubmed:owner |
NLM
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pubmed:authorsComplete |
Y
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pubmed:pagination |
627-37
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pubmed:dateRevised |
2011-6-6
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pubmed:meshHeading |
pubmed-meshheading:20717897-Animals,
pubmed-meshheading:20717897-Cells, Cultured,
pubmed-meshheading:20717897-Chemokine CCL3,
pubmed-meshheading:20717897-Endotoxemia,
pubmed-meshheading:20717897-Extracellular Signal-Regulated MAP Kinases,
pubmed-meshheading:20717897-G-Protein-Coupled Receptor Kinase 2,
pubmed-meshheading:20717897-Inflammation,
pubmed-meshheading:20717897-Interleukin-10,
pubmed-meshheading:20717897-Interleukin-12 Subunit p40,
pubmed-meshheading:20717897-Lipopolysaccharides,
pubmed-meshheading:20717897-MAP Kinase Kinase Kinases,
pubmed-meshheading:20717897-MAP Kinase Signaling System,
pubmed-meshheading:20717897-Macrophages,
pubmed-meshheading:20717897-Mice,
pubmed-meshheading:20717897-Mitogen-Activated Protein Kinase Kinases,
pubmed-meshheading:20717897-Models, Biological,
pubmed-meshheading:20717897-Myeloid Cells,
pubmed-meshheading:20717897-NF-kappa B p50 Subunit,
pubmed-meshheading:20717897-Neutrophils,
pubmed-meshheading:20717897-Organ Specificity,
pubmed-meshheading:20717897-Shock, Septic,
pubmed-meshheading:20717897-Survival Analysis
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pubmed:year |
2011
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pubmed:articleTitle |
Myeloid-specific GPCR kinase-2 negatively regulates NF-?B1p105-ERK pathway and limits endotoxemic shock in mice.
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pubmed:affiliation |
Department of Physiology and Division of Pathology, Michigan State University, East Lansing, Michigan 48824, USA.
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pubmed:publicationType |
Journal Article,
Research Support, Non-U.S. Gov't,
Research Support, N.I.H., Extramural
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