Endothelin-1 and monocyte chemoattractant protein-1 modulation in ischemiaand 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 bra in. Using the Middle Cerebral Artery Occlusion (MCAO) mouse model, this stu dy demonstrated that, in vivo, bath endothelin-1 (Et-1), a potent vasoconst rictor, and the macrophage chemokine, monocyte chemoattractant factor-1 (MC P-1) are induced in ischemia. Further studies, using human brain-derived en dothelial 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 produ ction is mediated by the ETA receptor. Inflammatory cytokines, tumor necros is factor alpha and interleukin-1 beta, functioned additively and synergist ically, respectively, with Et-1 to increase this MCP-1 production. Partial elucidation of the signal transduction pathways involved in Et-1-induced MC P-1 production demonstrated that protein kinase C-, but not cAMP-dependent pathways are involved. These data demonstrate that Et-1 functioning as an i nflammatory peptide, increased levels of MCP-1, suggesting a mechanism for chemokine regulation during ischemia/reperfusion injury. (C) 2001 Published by Elsevier Science B.V.