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* 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; and
University of Texas Health Science Center, San Antonio, TX 78229
In this study, we evaluated the molecular mechanisms involved in
morphine-induced macrophage apoptosis. Both morphine and TGF-
promoted P38 mitogen-activated protein kinase (MAPK) phosphorylation,
and this phosphorylation was inhibited by SB 202190 as well as by SB
203580. Anti-TGF- Ab as well as naltrexone (an opiate receptor
antagonist) inhibited morphine-induced macrophage P38 MAPK
phosphorylation. Anti-TGF- Ab also attenuated morphine-induced p53
as well as inducible NO synthase expression; in contrast,
NG-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- 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.
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