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-β promoted P38 mitogen-activated protein kinase (MAPK) phosphorylation, and this phosphorylation was inhibited by SB 202190 as well as by SB 203580. Anti-TGF-β Ab as well as naltrexone (an opiate receptor antagonist) inhibited morphine-induced macrophage P38 MAPK phosphorylation. Anti-TGF-β 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-β 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.

Opioid receptor blockade reduces Fas-induced hepatitis in mice

“…13,17 In vitro, experiments performed on immune cells-including lymphocytes and macrophages-showed that a direct interaction with morphine resulted in up-regulation of Fas mRNA. 11,18 Together, these data assume that spleen cell sensitization to Fas-mediated apoptosis induced by opioids was a paracrine/autocrine MOR-mediated effect associated with an increase in Fas mRNA. By comparison, we investigated whether the neutralization of opioid receptor activity was associated with a lower expression of Fas mRNA in the liver.…”

Dracorhodin Perchlorate Induces A375-S2 Cell Apoptosis via Accumulation of p53 and Activation of Caspases

“…27) The activation of p38 and JNK MAPKs in apoptosis is also linked with the induction of Fas/FasL. 49,50) Moreover, p53 can stimulate Fas transcription, and overexpressed p53 may enhance levels of Fas at the cell surface by promoting trafficking of the Fas receptor from the Golgi apparatus. 14) Therefore the activation of p38/JNK MAPK and p53 may upregulate Fas/FasL expression and then contribute to the synergistic effects of dracorhodin perchlorate with CH-11.…”

Opioids As Modulators of Cell Death and Survival—Unraveling Mechanisms and Revealing New Indications

“…JNKs are among several kinases that phosphorylate p53 at Nterminal serine residues leading to a stabilization of the protein. Therefore, JNK activation might constitute a signaling pathway by which morphine causes the observed p53 phosphorylation and stabilization (Singhal et al, 2002;Tegeder et al, 2003). The effects of morphine on p53 may also be mediated through the ubiquitin ligase Mdm2 which ensures rapid p53 degradation under homeostatic conditions.…”