Extracellular superoxide dismutase is upregulated with inducible nitric oxide synthase after NF-κB activation

Abstract

Inflammatory cytokines have been shown to upregulate secretion of the antioxidant enzyme extracellular superoxide dismutase (EC-SOD) in dermal fibroblasts and, in other cells, to stimulate production of nitric oxide (⋅ NO). Because superoxide rapidly scavenges ⋅ NO, forming the injurious peroxynitrite anion (OONO−), we hypothesize that stimulated cells upregulate EC-SOD expression concurrently with ⋅ NO release. To test for coregulation of EC-SOD and ⋅ NO within the same cell, the timing of inducible nitric oxide synthase (iNOS) and EC-SOD transcription was measured after exposure of a rat type II pneumocyte analog, the L2 cell line, to a combination of interferon-γ (IFN-γ) and tumor necrosis factor-α (TNF-α). Upregulation of iNOS and EC-SOD transcription occurred after 6 h of exposure, and transcription of both genes was linked by activation of the transcription factor nuclear factor-κB. Both EC-SOD and iNOS were elevated in rat lung homogenates 24 h after intratracheal instillation with IFN-γ and TNF-α. The observation that EC-SOD and iNOS are temporally coregulated after cytokine exposure suggests the possibility of a critical mechanism by which cells might protect ⋅ NO and avoid the formation of OONO−during inflammation.