Role of P38 Mitogen-Activated Protein Kinase Phosphorylation and Fas-Fas Ligand Interaction in Morphine-Induced Macrophage Apoptosis

摘要

In this study , we evaluated the molecular mechanisms involved in morphine -induced macrophage apoptosis.Both morphine and TGF-#beta# promoted P38 mitogen-activated protein kinase (MAPK) phosphorylation , and this phosphorylation was inhibited by SB 202190 as well as by SB 203580.Anti-TGF-#beta# Ab also attenuated morphine-induced macrophag P38 MAPK phosphorylation .Anti-TGF-#beta# also attenuated morphine-indudced p53 as well as inducible NO synthase expression ; in contrast N~G-nitro-L-arginine methyl ester, an inhibitor of NO synthase, inhibited morphine-induced P38 MAPK phosorylation and Bax expression. Morphine also enhanced the expression of both Fas and Fas ligand (FasL), whereas anti Fasl Ab prevented morphine-induced macrophage apoptosis. Moreover, naltrexone inhibited morpine-induced Fasl expression. In addition, macrophages either deficient in FasL or lacking p53 showed resistance to the effect of morphine . Inhibitors of both caspase-8 and caspase-9 partially prevented the apoptotic effect of morphine on macrophages.In addition, capase-3 inhibitor prevented morphine-induced macrophage apoptosis.These findings suggest that morphine-induced macrophage apoptosis proceeds through opiate receptors via P38 MAPK phosphorylation.Both TGF-#beta# and inducible NO synthase play an important role in morphine-induced downstream signaling ,which seems to activate proteins involved in both extrinsic(Fas and FasL) and intrinsic (p53 and Bax) cell death pathways