| Activation of p38(MAPK) mediates the angiostatic effect of the chemokine receptor CXCR3-B. | |
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MedLine Citation:
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PMID: 18291705 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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Chemokines binding the CXCR3 receptor have been shown to inhibit angiogenesis via the CXCR3-B isoform, but the underlying molecular mechanisms are unknown. Aim of this study was to elucidate the effects of CXCR3-B on activation of members of the mitogen-activated protein kinase family, and to explore the relevance of defined signaling pathways to the angiostatic effects of CXCR3-B ligands. Human embryonic kidney (HEK) 293 cells were transfected with expression vectors encoding for CXCR3-A or CXCR3-B. In cells expressing CXCR3-A, CXCL10 (IP-10) at nanomolar concentrations induced activation of ERK, Akt, and Src, as previously described in human vascular pericytes. In HEK-293 cells expressing CXCR3-B, exposure to CXCL10 in the micromolar concentration range led to activation of the p38(MAPK) pathway, as indicated by phosphorylation of p38(MAPK) itself, and of MKK3/6 and MAPKAPK-2, that lie upstream and downstream of p38(MAPK), respectively. Similar results were obtained in cells stimulated with CXCL4 (PF4), a specific ligand of CXCR3-B. In contrast, CXCL4 was unable to activate p38(MAPK) in mock-transfected HEK-293 cells. Only a modest induction of ERK or JNK was observed upon CXCR3-B activation. In human microvascular endothelial cells, which selectively express CXCR3-B, in a cell cycle-dependent fashion, CXCL10 and CXCL4 increased the enzymatic activity of p38(MAPK). Pharmacologic inhibition of p38(MAPK) by SB302580 resulted in a significant increase in DNA synthesis and in reversal of the inhibitory action of CXCL10. In conclusion, the p38(MAPK) pathway is a downstream effector of CXCR3-B implicated in the angiostatic action of this chemokine receptor. |
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Authors:
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Ilaria Petrai; Krista Rombouts; Laura Lasagni; Francesco Annunziato; Lorenzo Cosmi; Roberto G Romanelli; Costanza Sagrinati; Benedetta Mazzinghi; Massimo Pinzani; Sergio Romagnani; Paola Romagnani; Fabio Marra |
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Publication Detail:
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Type: Journal Article; Research Support, Non-U.S. Gov't Date: 2008-01-16 |
Journal Detail:
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Title: The international journal of biochemistry & cell biology Volume: 40 ISSN: 1357-2725 ISO Abbreviation: Int. J. Biochem. Cell Biol. Publication Date: 2008 |
Date Detail:
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Created Date: 2008-06-20 Completed Date: 2008-09-30 Revised Date: 2009-11-19 |
Medline Journal Info:
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Nlm Unique ID: 9508482 Medline TA: Int J Biochem Cell Biol Country: England |
Other Details:
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Languages: eng Pagination: 1764-74 Citation Subset: IM |
Affiliation:
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Dipartimento di Medicina Interna, University of Florence, Viale Morgagni 85, I-50134 Florence, Italy. |
Export Citation:
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| MeSH Terms | |
Descriptor/Qualifier:
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Angiostatic Proteins
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metabolism* Cell Line Chemokine CXCL10 / metabolism Enzyme Activation Gene Expression Regulation Humans Platelet Factor 4 / metabolism Protein Isoforms / metabolism Receptors, CXCR3 / metabolism* Signal Transduction p38 Mitogen-Activated Protein Kinases / metabolism* |
| Chemical | |
Reg. No./Substance:
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0/Angiostatic Proteins; 0/CXCL10 protein, human; 0/CXCR3 protein, human; 0/Chemokine CXCL10; 0/Protein Isoforms; 0/Receptors, CXCR3; 37270-94-3/Platelet Factor 4; EC 2.7.11.24/p38 Mitogen-Activated Protein Kinases |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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