| Myeloid-specific GPCR kinase-2 negatively regulates NF-κB1p105-ERK pathway and limits endotoxemic shock in mice. | |
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MedLine Citation:
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PMID: 20717897 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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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-κB1p105-ERK pathway to be selectively regulated by GRK2. LPS-induced activation of NF-κB1p105-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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Authors:
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Sonika Patial; Yogesh Saini; Sitaram Parvataneni; Daniel M Appledorn; Gerald W Dorn; John J Lapres; Andrea Amalfitano; Patricia Senagore; Narayanan Parameswaran |
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Publication Detail:
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Type: Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't |
Journal Detail:
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Title: Journal of cellular physiology Volume: 226 ISSN: 1097-4652 ISO Abbreviation: J. Cell. Physiol. Publication Date: 2011 Mar |
Date Detail:
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Created Date: 2010-12-30 Completed Date: 2011-01-27 Revised Date: 2012-05-14 |
Medline Journal Info:
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Nlm Unique ID: 0050222 Medline TA: J Cell Physiol Country: United States |
Other Details:
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Languages: eng Pagination: 627-37 Citation Subset: IM |
Copyright Information:
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Copyright © 2010 Wiley-Liss, Inc. |
Affiliation:
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Department of Physiology and Division of Pathology, Michigan State University, East Lansing, Michigan 48824, USA. |
Export Citation:
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APA/MLA Format Download EndNote Download BibTex |
| MeSH Terms | |
Descriptor/Qualifier:
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Animals Cells, Cultured Chemokine CCL3 / metabolism Endotoxemia / complications, enzymology*, pathology Extracellular Signal-Regulated MAP Kinases / antagonists & inhibitors, metabolism* G-Protein-Coupled Receptor Kinase 2 / metabolism* Inflammation / complications, enzymology, pathology Interleukin-10 / metabolism Interleukin-12 Subunit p40 / metabolism Lipopolysaccharides / pharmacology MAP Kinase Kinase Kinases / metabolism MAP Kinase Signaling System* / drug effects Macrophages / drug effects, enzymology Mice Mitogen-Activated Protein Kinase Kinases / metabolism Models, Biological Myeloid Cells / drug effects, enzymology*, pathology NF-kappa B p50 Subunit / antagonists & inhibitors, metabolism* Neutrophils / drug effects, metabolism Organ Specificity / drug effects Shock, Septic / complications, enzymology*, pathology Survival Analysis |
| Grant Support | |
ID/Acronym/Agency:
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AR055726/AR/NIAMS NIH HHS; AR056680/AR/NIAMS NIH HHS; HL095637/HL/NHLBI NIH HHS; R01 AR056680/AR/NIAMS NIH HHS; R01 AR056680-01A2/AR/NIAMS NIH HHS; R01 AR056680-02/AR/NIAMS NIH HHS; R01 AR056680-03/AR/NIAMS NIH HHS; R01 HL087871-06/HL/NHLBI NIH HHS; R01 HL095637/HL/NHLBI NIH HHS; R01 HL095637-01/HL/NHLBI NIH HHS; R01 HL095637-02/HL/NHLBI NIH HHS; R01 HL095637-03/HL/NHLBI NIH HHS; R21 AR055726-01A1/AR/NIAMS NIH HHS; R21 AR055726-02/AR/NIAMS NIH HHS |
| Chemical | |
Reg. No./Substance:
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0/Ccl3 protein, mouse; 0/Chemokine CCL3; 0/Interleukin-12 Subunit p40; 0/Lipopolysaccharides; 0/NF-kappa B p50 Subunit; 130068-27-8/Interleukin-10; 147257-52-1/Nfkb1 protein, mouse; EC 2.7.11.15/G-Protein-Coupled Receptor Kinase 2; EC 2.7.11.24/Extracellular Signal-Regulated MAP Kinases; EC 2.7.11.25/MAP Kinase Kinase Kinases; EC 2.7.12.2/Mitogen-Activated Protein Kinase Kinases |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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