title: Role of p38 mitogen-activated protein kinase phosphorylation and Fas-Fas ligand interaction in morphine-induced macrophage apoptosis.
abstract: 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 as well as naltrexone (an opiate receptor antagonist) inhibited morphine-induced macrophage P38 MAPK phosphorylation. Anti-TGF-beta Ab also attenuated morphine-induced 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 phosphorylation 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 morphine-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, caspase-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.
authors.affiliation: Immunology and Inflammation Center, North Shore-Long Island Jewish Research Institute and Division of Kidney Diseases and Hypertension, Long Island Jewish Medical Center, New Hyde Park, NY 11040, USA. singhal@lij.edu
authors.forename: Pravin C
authors.initials: PC
authors.lastname: Singhal
authors.forename: Madhu
authors.initials: M
authors.lastname: Bhaskaran
authors.forename: Jaimita
authors.initials: J
authors.lastname: Patel
authors.forename: Kalpesh
authors.initials: K
authors.lastname: Patel
authors.forename: Balakuntalam S
authors.initials: BS
authors.lastname: Kasinath
authors.forename: Senthil
authors.initials: S
authors.lastname: Duraisamy
authors.forename: Nicholas
authors.initials: N
authors.lastname: Franki
authors.forename: Krishna
authors.initials: K
authors.lastname: Reddy
authors.forename: Aditi A
authors.initials: AA
authors.lastname: Kapasi
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects* / Q000276:immunology; D020169:Caspases / Q000502:physiology; D002460:Cell Line; D002478:Cells, Cultured; D004790:Enzyme Induction / Q000187:drug effects / Q000276:immunology; D053222:Fas Ligand Protein; D008024:Ligands; D020935:MAP Kinase Signaling System / Q000187:drug effects / Q000276:immunology*; D017737:Macrophages, Peritoneal / Q000166:cytology / Q000187:drug effects / Q000201:enzymology* / Q000276:immunology*; D008562:Membrane Glycoproteins / Q000096:biosynthesis / Q000378:metabolism* / Q000502:physiology; D051379:Mice; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000378:metabolism* / Q000502:physiology; D009020:Morphine / Q000494:pharmacology*; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000502:physiology; D052247:Nitric Oxide Synthase Type II; D010766:Phosphorylation / Q000187:drug effects; D011518:Proto-Oncogene Proteins / Q000502:physiology; D019253:Proto-Oncogene Proteins c-bcl-2; D011957:Receptors, Opioid / Q000502:physiology; D016212:Transforming Growth Factor beta / Q000502:physiology; D051028:bcl-2-Associated X Protein; D019014:fas Receptor / Q000096:biosynthesis / Q000378:metabolism* / Q000502:physiology; D048051:p38 Mitogen-Activated Protein Kinases
chemical_list: C494827:Bax protein, mouse; D053222:Fas Ligand Protein; C505658:Fasl protein, mouse; D008024:Ligands; D008562:Membrane Glycoproteins; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D011957:Receptors, Opioid; D016212:Transforming Growth Factor beta; D051028:bcl-2-Associated X Protein; D019014:fas Receptor; D009020:Morphine; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; C496317:Nos2 protein, mouse; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D020169:Caspases