Document Detail

Activation of p38(MAPK) mediates the angiostatic effect of the chemokine receptor CXCR3-B.
MedLine Citation:
PMID:  18291705     Owner:  NLM     Status:  MEDLINE    
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.
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:
Type:  Journal Article; Research Support, Non-U.S. Gov't     Date:  2008-01-16
Journal Detail:
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:
Created Date:  2008-06-20     Completed Date:  2008-09-30     Revised Date:  2009-11-19    
Medline Journal Info:
Nlm Unique ID:  9508482     Medline TA:  Int J Biochem Cell Biol     Country:  England    
Other Details:
Languages:  eng     Pagination:  1764-74     Citation Subset:  IM    
Dipartimento di Medicina Interna, University of Florence, Viale Morgagni 85, I-50134 Florence, Italy.
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MeSH Terms
Angiostatic Proteins / metabolism*
Cell Line
Chemokine CXCL10 / metabolism
Enzyme Activation
Gene Expression Regulation
Platelet Factor 4 / metabolism
Protein Isoforms / metabolism
Receptors, CXCR3 / metabolism*
Signal Transduction
p38 Mitogen-Activated Protein Kinases / metabolism*
Reg. No./Substance:
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 Mitogen-Activated Protein Kinases

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