Nonsteroidal anti-inflammatory drugs inhibit expression of the inducible nitric oxide synthase gene.
Increased nitric oxide production is associated with acute and chronic inflammatory processes. Accordingly, we tested the hypothesis that the therapeutic action of nonsteroidal anti-inflammatory drugs could be attributed at least in part to inhibition of excess nitric oxide production. We report here that sodium salicylate, aspirin, ibuprofen, and indomethacin markedly inhibited the appearance of the inducible inflammatory nitric oxide synthase in rat alveolar macrophages activated with lipopolysaccharide and interferon gamma. We attribute the mechanism of nitric oxide synthase inhibition by nonsteroidal anti-inflammatory drugs to pretranslational control of enzyme expression and not to direct inhibition of enzymatic activity. These observations indicate that the chronic anti-inflammatory action of nonsteroidal anti-inflammatory drugs may be due not only to inhibition of prostaglandin synthesis but also to inhibition of inducible nitric oxide synthase gene expression and nitric oxide synthesis.
Aeberhard
E E
EE
Department of Pediatrics, School of Medicine, University of California, Los Angeles 90024.
Henderson
S A
SA
Arabolos
N S
NS
Griscavage
J M
JM
Castro
F E
FE
Barrett
C T
CT
Ignarro
L J
LJ
D000594:Amino Acid Oxidoreductases / Q000096:biosynthesis*; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology*; D001241:Aspirin / Q000494:pharmacology; D002460:Cell Line; D004305:Dose-Response Relationship, Drug; D004790:Enzyme Induction / Q000187:drug effects; D015870:Gene Expression / Q000187:drug effects*; D007052:Ibuprofen / Q000494:pharmacology; D007213:Indomethacin / Q000494:pharmacology; D007527:Isoenzymes / Q000096:biosynthesis; D007700:Kinetics; D016676:Macrophages, Alveolar / Q000187:drug effects / Q000201:enzymology*; D019001:Nitric Oxide Synthase; D051381:Rats; D012980:Sodium Salicylate / Q000494:pharmacology
D000894:Anti-Inflammatory Agents, Non-Steroidal; D007527:Isoenzymes; D019001:Nitric Oxide Synthase; D000594:Amino Acid Oxidoreductases; D001241:Aspirin; D012980:Sodium Salicylate; D007052:Ibuprofen; D007213:Indomethacin