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Thiol regulation of pro-inflammatory cytokines reveals a novel immunopharmacological potential of glutathione in the alveolar epithelium.
- Source :
-
The Journal of pharmacology and experimental therapeutics [J Pharmacol Exp Ther] 2001 Mar; Vol. 296 (3), pp. 996-1005. - Publication Year :
- 2001
-
Abstract
- 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 (DeltapO(2)/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.
- Subjects :
- Analysis of Variance
Animals
Cells, Cultured
Cytokines drug effects
Epithelium drug effects
Epithelium metabolism
Glutathione deficiency
Hydrogen Peroxide metabolism
Hydroxyl Radical metabolism
Oxidation-Reduction
Pulmonary Alveoli drug effects
Rats
Rats, Sprague-Dawley
Reactive Oxygen Species metabolism
Superoxides metabolism
Cytokines metabolism
Glutathione metabolism
Pulmonary Alveoli metabolism
Sulfhydryl Compounds pharmacology
Subjects
Details
- Language :
- English
- ISSN :
- 0022-3565
- Volume :
- 296
- Issue :
- 3
- Database :
- MEDLINE
- Journal :
- The Journal of pharmacology and experimental therapeutics
- Publication Type :
- Academic Journal
- Accession number :
- 11181934