Molecular Mechanism of the Regulation of Glutathione Synthesis by Tumor Necrosis Factor-α and Dexamethasone in Human Alveolar Epithelial Cells*

Glutathione (GSH) is an important physiological antioxidant in lung epithelial cells and lung lining fluid. We studied the regulation of GSH synthesis in response to the pro-inflammatory cytokine tumor necrosis factor-α (TNF-α) and the anti-inflammatory agent dexamethasone in human alveolar epithelial cells (A549). TNF-α (10 ng/ml) exposure increased GSH levels, concomitant with a significant increase in γ-glutamylcysteine synthetase (γ-GCS) activity and the expression of γ-GCS heavy subunit (γ-GCS-HS) mRNA at 24 h. Treatment with TNF-α also increased chloramphenicol acetyltransferase (CAT) activity of a γ-GCS-HS 5′-flanking region reporter construct, transfected into alveolar epithelial cells. Mutation of the putative proximal AP-1-binding site (−269 to −263 base pairs), abolished TNF-α-mediated activation of the promoter. Gel shift and supershift analysis showed that TNF-α increased AP-1 DNA binding which was predominantly formed by dimers of c-Jun. Dexamethasone (3 μm) produced a significant decrease in the levels of GSH, decreased γ-GCS activity and γ-GCS-HS mRNA expression at 24 h. The increase in GSH levels, γ-GCS-HS mRNA, γ-GCS-HS promoter activity, and AP-1 DNA binding produced by TNF-α were abrogated by co-treating the cells with dexamethasone. Thus these data demonstrate that TNF-α and dexamethasone modulate GSH levels and γ-GCS-HS mRNA expression by their effects on AP-1 (c-Jun homodimer). These data have implications for the oxidant/antioxidant balance in inflammatory lung diseases.

• Publication year

  1999

• Venue

  Journal of Biological Chemistry

• Publication date

  1999-02-19

• Fields of study

  Biology, Medicine

• Identifiers
  DOI 10.1074/JBC.274.8.5088PMID 9988757
• External record

  Open on Semantic Scholar

• Source metadata

  Semantic Scholar, PubMed

• No claims are published for this paper.

• No concepts are published for this paper.

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