Endothelin-1 and monocyte chemoattractant protein-1 modulation in ischemia and human brain-derived endothelial cell cultures.
Brain tissue damage due to ischemia/reperfusion has been shown to be caused, in part, by activated macrophages infiltrating into the post-ischemic brain. Using the Middle Cerebral Artery Occlusion (MCAO) mouse model, this study demonstrated that, in vivo, both endothelin-1 (Et-1), a potent vasoconstrictor, and the macrophage chemokine, monocyte chemoattractant factor-1 (MCP-1) are induced in ischemia. Further studies, using human brain-derived endothelial cells (CNS-EC), showed that in vitro, Et-1 can directly stimulate MCP-1 mRNA expression and MCP-1 protein; and this Et-1-induced MCP-1 production is mediated by the ET(A) receptor. Inflammatory cytokines, tumor necrosis factor alpha and interleukin-1beta, functioned additively and synergistically, respectively, with Et-1 to increase this MCP-1 production. Partial elucidation of the signal transduction pathways involved in Et-1-induced MCP-1 production demonstrated that protein kinase C-, but not cAMP-dependent pathways are involved. These data demonstrate that Et-1, functioning as an inflammatory peptide, increased levels of MCP-1, suggesting a mechanism for chemokine regulation during ischemia/reperfusion injury.
Chen
P
P
Department of Pathology, University of Southern California, School of Medicine, Los Angeles, CA 90033, USA.
Shibata
M
M
Zidovetzki
R
R
Fisher
M
M
Zlokovic
B V
BV
Hofman
F M
FM
D000818:Animals; D001921:Brain / Q000378:metabolism* / Q000473:pathology; D002545:Brain Ischemia / Q000378:metabolism* / Q000473:pathology; D002478:Cells, Cultured; D018932:Chemokine CCL2 / Q000235:genetics / Q000378:metabolism*; D017868:Cyclic AMP-Dependent Protein Kinases / Q000502:physiology; D016207:Cytokines / Q000494:pharmacology; D019332:Endothelin-1 / Q000378:metabolism* / Q000494:pharmacology; D004727:Endothelium / Q000378:metabolism / Q000473:pathology; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D011493:Protein Kinase C / Q000502:physiology; D012333:RNA, Messenger / Q000378:metabolism; D044022:Receptor, Endothelin A; D017466:Receptors, Endothelin / Q000502:physiology; D015854:Up-Regulation
D018932:Chemokine CCL2; D016207:Cytokines; D019332:Endothelin-1; D012333:RNA, Messenger; D044022:Receptor, Endothelin A; D017466:Receptors, Endothelin; D017868:Cyclic AMP-Dependent Protein Kinases; D011493:Protein Kinase C