Regulation of nuclear factor-kappa B, activator protein-1, and glutathionelevels by tumor necrosis factor-alpha and dexamethasone in alveolar epithelial cells

The development of an oxidant/antioxidant imbalance in lung inflammation ma y activate redox-sensitive transcription factors such as nuclear factor-kap paB (NF-kappa B) and activator protein-1 (AP-1), which regulate the gents f or proinflammatory mediators and protective antioxidant genes. GSH, a ubiqu itous tripeptide thiol, is a vital intra- and extracellular protective anti oxidant against oxidative stress, which plays a key role in the control of proinflammatory processes in the lungs. The rate-limiting enzyme in GSH syn thesis is gamma-glutamylcysteine synthetase (gamma-GCS), which consists of a catalytic heavy and a regulatory light subunit. The promoter regions of t he human gamma-GCS subunits contain AP-1, NF-kappa B, and antioxidant respo nse elements and are regulated by oxidants, growth factors, inflammatory cy tokine tumor necrosis factor-alpha (TNF-alpha), and anti-inflammatory agent (dexamethasone) in lung cells. TNF-alpha depletes intracellular GSH, conco mitant with an increase in oxidised glutathione levels in alveolar epitheli al cells. TNF-alpha also induces the activation of NF-kappa B and AP-1 and the subsequent increase in gamma-GCS heavy subunit transcription in these c ells. Dexamethasone depleted both basal and TNF-alpha-stimulated GSH levels by down-regulating the gamma-GCS-heavy subunit transcription via a mechani sm involving AP-1 (c-Jun). The existence of this fine tuning between the re dox GSH levels and the activation of transcription factors may determine th e balance of transcription for proinflammatory and antioxidant gamma-GCS ge nts in inflammation. More studies are required to understand the signalling mechanism of the redox regulation of NF-kappa B and AP-1 and gene transcri ption in inflammation. This could lead to the development of therapeutic st rategies based on the pharmacological manipulation of the production of thi s important antioxidant in inflammation. BIOCHEM PHARMACOL 60;8:1041-1049, 2000. (C) 2000 Elsevier Science Inc.