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Vol. 296, Issue 3, 996-1005, March 2001

Thiol Regulation of Pro-Inflammatory Cytokines Reveals a Novel Immunopharmacological Potential of Glutathione in the Alveolar Epithelium

John J. E. Haddad, Bared Safieh-Garabedian, Nayef E. Saadé and Stephen C. Land

Oxygen Signaling Group, Center for Research into Human Development, Tayside Institute of Child Health, Faculty of Medicine, Ninewells Hospital and Medical School, University of Dundee, Dundee, Scotland, United Kingdom (J.J.H., S.C.L.); and the Departments of Biology (B.S.-G.), Faculty of Arts and Sciences, Human Morphology and Physiology (N.E.S.), Faculty of Medicine, American University of Beirut, Beirut, Lebanon

The therapeutic immunopharmacological potential of glutathione in the alveolar epithelium is not well characterized. We developed an in vitro model of fetal alveolar type II epithelial cells to investigate the effect of redox disequilibrium on chemioxyexcitation (Delta pO2/ROS) induced up-regulation of pro-inflammatory cytokines. Buthionine sulfoximine, an irreversible inhibitor of gamma -glutamylcysteine synthetase, the rate-limiting enzyme in glutathione (GSH) biosynthesis, induced intracellular reactive oxygen species (ROS) and the release of interleukin-1beta (IL-1beta ), IL-6, and tumor necrosis factor-alpha . Chloroethyl nitrosourea, which blocks the NADPH-dependent recycling of oxidized glutathione (GSSG), reduced ROS-induced cytokine production, similar to pyrrolidine dithiocarbamate, an antioxidant/pro-oxidant thiuram, which elevates GSSG. The antioxidant and GSH precursor, acetylcysteine, abrogated cytokine release concomitant with suppression of ROS, an effect mimicked by gamma -glutamylcysteinyl-ethyl ester, a cell permeant GSH. Cysteine, the rate-limiting amino acid in the de novo synthesis of GSH, administered as oxothiazolidine carboxylate and adenosylmethionine, mitigated the chemioxyexcitation-dependent cytokine release. Ebselen, an anti-inflammatory antioxidant, which mimics the effect of glutathione peroxidase, neutralized ROS by the GSH-peroxidase-coupled reaction, thereby blocking the pathway to cytokine enhancement. Our results indicate that modulating redox equilibrium by pharmacological thiols exhibits differential regulation on pro-inflammatory cytokines, thus bearing clinical consequences for the therapeutic treatment of pediatric distresses in pathophysiology.

0022-3565/01/2963-0996$03.00/0
THE JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS
Copyright © 2001 by The American Society for Pharmacology and Experimental Therapeutics


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