EXTRACELLULAR-SUPEROXIDE DISMUTASE IS UP-REGULATED WITH INDUCIBLE NITRIC-OXIDE SYNTHASE AFTER NF-KAPPA-B ACTIVATION

Inflammatory cytokines have been shown to upregulate secretion of the antioxidant enzyme extracellular superoxide dismutase (EC-SOD) in derm al fibroblasts and, in other cells, to stimulate production of nitric oxide (.NO). Because superoxide rapidly scavenges .NO, forming the inj urious peroxynitrite anion (OONO-), we hypothesize that stimulated cel ls upregulate EC-SOD expression concurrently with .NO release. To test for coregulation of EC-SOD and .NO within the same cell, the timing o f inducible nitric oxide synthase (iNOS) and EC-SOD transcription was measured after exposure of a rat type II pneumocyte analog, the L2 cel l line, to a combination of interferon-gamma (IFN-gamma) and tumor nec rosis factor-alpha (TNF-alpha). Upregulation of iNOS and EC-SOD transc ription occurred after 6 h of exposure and transcription of both genes was linked by activation of the transcription factor nuclear factor-k appa B. Both EC-SOD and iNOS were elevated in rat lung homogenates 24 h after intratracheal instillation with IFN-gamma and TNF-alpha. The o bservation that EC-SOD and iNOS are temporally coregulated after cytok ine exposure suggests the possibility of a critical mechanism by which cells might protect NO and avoid the formation of OONO- during inflam mation.