Treatment with glutathione precursor decreases cytokine activity

Background: Inflammatory cytokine activity is increased in many forms of experimental and clinical liver injury including alcoholic liver disease (ALD). Monocytes and Kupffer cells produce cytokines such as tumor necrosis factor (TNF), interleukin (IL)-8, and IL-G in response to stimuli such as endotoxin (lipopolysaccharide [LPS]). This cytokine production is regulated by the oxidative stress-sensitive transcription factor NF kappa B. Glutathione (GSH) prodrugs such as oxathizolidine-4-carboxylic acid (OTZ) can inhibit activation of NF kappa B and subsequent cytokine production in monocytes and Kupffer cells in vitro. The objective of this study was to treat stable cirrhotic patients with OTZ in vivo to evaluate its effects on monocyte cytokine production (TNF, IL-8, and IL-6) and whole blood GSH levels. Methods: Nine patients with stable cirrhosis received OTZ (70 mg/kg ni every 8 hours) for 9 days. Peripheral blood monocytes were obtained on study days 1 and 9, using density gradient centrifugation and adherence to plastic, and were stimulated with LPS (5 mu g/mL). TNF, IL-8, and IL-6 were measured in culture supernatants by enzyme-linked serum immunosorbent assay. Whole blood GSH levels were measured by high-performance liquid chromatography. Results: There was a significant decrease in monocyte TNF, IL-8, and IL-6 production after OTZ therapy. Patients with cirrhosis had significantly lower admission whole blood GSH levels compared with controls and GSH normalized with OTZ administration. Conclusions: Treatment with the GSH prodrug OTZ inhibited monocyte cytokine production and increased whole blood GSH. This may have important therapeutic implications for multiple cytokine-mediated disease processes.