| Cross-desensitization among CXCR1, CXCR2, and CCR5: role of protein kinase C-epsilon. | |
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MedLine Citation:
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PMID: 15905535 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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The IL-8 (or CXCL8) chemokine receptors, CXCR1 and CXCR2, activate protein kinase C (PKC) to mediate leukocyte functions. To investigate the roles of different PKC isoforms in CXCL8 receptor activation and regulation, human mononuclear phagocytes were treated with CXCL8 or CXCL1 (melanoma growth-stimulating activity), which is specific for CXCR2. Plasma membrane association was used as a measure of PKC activation. Both receptors induced time-dependent association of PKCalpha, -beta1, and -beta2 to the membrane, but only CXCR1 activated PKCepsilon. CXCL8 also failed to activate PKCepsilon in RBL-2H3 cells stably expressing CXCR2. DeltaCXCR2, a cytoplasmic tail deletion mutant of CXCR2 that is resistant to internalization, activated PKCepsilon as well as CXCR1. Expression of the PKCepsilon inhibitor peptide epsilonV1 in RBL-2H3 cells blocked PKCepsilon translocation and inhibited receptor-mediated exocytosis, but not phosphoinositide hydrolysis or peak intracellular Ca(2+) mobilization. epsilonV1 also inhibited CXCR1-, CCR5-, and DeltaCXCR2-mediated cross-regulatory signals for GTPase activity, Ca(2+) mobilization, and internalization. Peritoneal macrophages from PKCepsilon-deficient mice (PKCepsilon(-/-)) also showed decreased CCR5-mediated cross-desensitization of G protein activation and Ca(2+) mobilization. Taken together, the results indicate that CXCR1 and CCR5 activate PKCepsilon to mediate cross-inhibitory signals. Inhibition or deletion of PKCepsilon decreases receptor-induced exocytosis and cross-regulatory signals, but not phosphoinositide hydrolysis or peak intracellular Ca(2+) mobilization, suggesting that cross-regulation is a Ca(2+)-independent process. Because DeltaCXCR2, but not CXCR2, activates PKCepsilon and cross-desensitizes CCR5, the data further suggest that signal duration leading to activation of novel PKC may modulate receptor-mediated cross-inhibitory signals. |
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Authors:
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Mohd W Nasser; Robin J Marjoram; Stephan L Brown; Ricardo M Richardson |
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Publication Detail:
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Type: Journal Article; Research Support, N.I.H., Extramural; Research Support, U.S. Gov't, Non-P.H.S.; Research Support, U.S. Gov't, P.H.S. |
Journal Detail:
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Title: Journal of immunology (Baltimore, Md. : 1950) Volume: 174 ISSN: 0022-1767 ISO Abbreviation: J. Immunol. Publication Date: 2005 Jun |
Date Detail:
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Created Date: 2005-05-20 Completed Date: 2005-08-08 Revised Date: 2012-06-25 |
Medline Journal Info:
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Nlm Unique ID: 2985117R Medline TA: J Immunol Country: United States |
Other Details:
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Languages: eng Pagination: 6927-33 Citation Subset: AIM; IM |
Affiliation:
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Julius L. Chambers Biomedical/Biotechnology Research Institute, North Carolina Central University, Durham, 27707, USA. |
Export Citation:
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| MeSH Terms | |
Descriptor/Qualifier:
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Animals Calcium Signaling / genetics, immunology Cell Line, Tumor Endocytosis / genetics, immunology Enzyme Activation / genetics, immunology Genetic Vectors Humans Isoenzymes / deficiency, metabolism, physiology Macrophages, Peritoneal / enzymology, immunology, metabolism Mice Mice, Knockout Protein Kinase C / deficiency, genetics, metabolism, physiology* Protein Kinase C-epsilon Rats Receptors, CCR5 / genetics, metabolism, physiology* Receptors, Interleukin-8A / metabolism, physiology* Receptors, Interleukin-8B / metabolism, physiology* Transfection |
| Grant Support | |
ID/Acronym/Agency:
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AI38910/AI/NIAID NIH HHS; CA92077/CA/NCI NIH HHS |
| Chemical | |
Reg. No./Substance:
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0/Isoenzymes; 0/Receptors, CCR5; 0/Receptors, Interleukin-8A; 0/Receptors, Interleukin-8B; EC 2.7.1.-/Prkce protein, mouse; EC 2.7.1.-/Prkce protein, rat; EC 2.7.11.13/PRKCE protein, human; EC 2.7.11.13/Protein Kinase C; EC 2.7.11.13/Protein Kinase C-epsilon |
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