Regulation of nuclear factor-κB, activator protein-1, and glutathione levels by tumor necrosis factor-α and dexamethasone in alveolar epithelial cells

Abstract

The development of an oxidant/antioxidant imbalance in lung inflammation may activate redox-sensitive transcription factors such as nuclear factor- kappaB (NF-κB) and activator protein-1 (AP-1), which regulate the genes for proinflammatory mediators and protective antioxidant genes. GSH, a ubiquitous tripeptide thiol, is a vital intra- and extracellular protective antioxidant against oxidative stress, which plays a key role in the control of proinflammatory processes in the lungs. The rate-limiting enzyme in GSH synthesis is γ-glutamylcysteine synthetase (γ-GCS), which consists of a catalytic heavy and a regulatory light subunit. The promoter regions of the human γ-GCS subunits contain AP-1, NF-κB, and antioxidant response elements and are regulated by oxidants, growth factors, inflammatory cytokine tumor necrosis factor-α (TNF-α), and anti-inflammatory agent (dexamethasone) in lung cells. TNF-α depletes intracellular GSH, concomitant with an increase in oxidised glutathione levels in alveolar epithelial cells. TNF-α also induces the activation of NF-κB and AP-1 and the subsequent increase in γ-GCS heavy subunit transcription in these cells. Dexamethasone depleted both basal and TNF-α-stimulated GSH levels by down-regulating the γ-GCS-heavy subunit transcription via a mechanism involving AP-1 (c-Jun). The existence of this fine tuning between the redox GSH levels and the activation of transcription factors may determine the balance of transcription for proinflammatory and antioxidant γ-GCS genes in inflammation. More studies are required to understand the signalling mechanism of the redox regulation of NF-κB and AP-1 and gene transcription in inflammation. This could lead to the development of therapeutic strategies based on the pharmacological manipulation of the production of this important antioxidant in inflammation.