Extracellular superoxide dismutase is upregulated 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 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 rate type II pneumocyte analog, the L2 cell line, to a combination of interferon-gamma (IFN-gamma) and tumor necrosis factor-alpha (TNF-alpha). 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-kappa B. Both EC-SOD and iNOS were elevated in rat lung homogenates 24 h after intratracheal instillation with IFN-gamma and TNF-alpha. 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.
Brady
T C
TC
Department of Pathology, Duke University Medical Center, Durham, North Carolina 27710, USA.
Chang
L Y
LY
Day
B J
BJ
Crapo
J D
JD
D000818:Animals; D000975:Antioxidants / Q000494:pharmacology; D002460:Cell Line; D004790:Enzyme Induction; D007371:Interferon-gamma / Q000494:pharmacology*; D007700:Kinetics; D008168:Lung / Q000201:enzymology*; D016328:NF-kappa B / Q000378:metabolism*; D019001:Nitric Oxide Synthase / Q000096:biosynthesis*; D016133:Polymerase Chain Reaction; D011392:Proline / Q000031:analogs & derivatives / Q000494:pharmacology; D012333:RNA, Messenger / Q000096:biosynthesis; D051381:Rats; D013482:Superoxide Dismutase / Q000096:biosynthesis*; D013859:Thiocarbamates / Q000494:pharmacology; D013997:Time Factors; D014158:Transcription, Genetic / Q000187:drug effects / Q000502:physiology*; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*
D000975:Antioxidants; D016328:NF-kappa B; D012333:RNA, Messenger; D013859:Thiocarbamates; D014409:Tumor Necrosis Factor-alpha; C066229:prolinedithiocarbamate; D007371:Interferon-gamma; D011392:Proline; D019001:Nitric Oxide Synthase; D013482:Superoxide Dismutase