Evaluation of the ability of carprofen and flunixin meglumine to inhibit activation of nuclear factor kappa B.
OBJECTIVE
To determine whether the nonsteroidal anti-inflammatory drugs (NSAIDs) carprofen, flunixin meglumine, and phenylbutazone have cyclooxygenase (COX)-independent effects that specifically inhibit activation of the proinflammatory transcription factor nuclear factor kappa B (NfkappaB).


METHODS
Purified ovine COX-1 and -2 and cultures of RAW 264.7 murine macrophages.


METHODS
The COX-1 and -2 inhibitory effects of the NSAIDs were tested in assays that used purified ovine COX-1 and -2. Prostaglandin production was analyzed by use of a radioimmunoassay. Inhibitory effects of these drugs on lipopolysaccharide (LPS)-induction of inducible nitric oxide synthase (iNOS) and LPS-stimulated translocation of NficB were determined by use of RAW 264.7 murine macrophages.


RESULTS
Flunixin meglumine and phenylbutazone were selective inhibitors of COX-1. Carprofen and flunixin meglumine, but not phenylbutazone, inhibited LPS-induction of iNOS. Carprofen and, to a lesser degree, flunixin meglumine had inhibitory effects on NFkappaB activation.


CONCLUSIONS
The ability of drugs such as carprofen and flunixin meglumine to inhibit activation of NfkappaB-dependent genes such as iNOS, in addition to their effects on COX, suggests an additional mechanism for their anti-inflammatory effects and may explain the ability of flunixin meglumine to be an effective inhibitor of the effects of endotoxin in horses with endotoxemia.
Bryant
Clare E
CE
Department of Clinical Veterinary Medicine, University of Cambridge, Madingley Rd, Cambridge, UK CB3 OES.
Farnfield
Belinda A
BA
Janicke
Heidi J
HJ
D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology*; D002227:Carbazoles / Q000494:pharmacology*; D002460:Cell Line; D003002:Clonixin / Q000031:analogs & derivatives* / Q000494:pharmacology*; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology; D004790:Enzyme Induction / Q000187:drug effects; D007249:Inflammation / Q000188:drug therapy; D020128:Inhibitory Concentration 50; D008070:Lipopolysaccharides / Q000494:pharmacology; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D016328:NF-kappa B / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D019001:Nitric Oxide Synthase / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II; D010653:Phenylbutazone / Q000494:pharmacology; D011451:Prostaglandin-Endoperoxide Synthases / Q000378:metabolism; D011453:Prostaglandins / Q000096:biosynthesis; D012756:Sheep
D000894:Anti-Inflammatory Agents, Non-Steroidal; D002227:Carbazoles; D016861:Cyclooxygenase Inhibitors; D008070:Lipopolysaccharides; D016328:NF-kappa B; D011453:Prostaglandins; C014558:flunixin meglumine; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; C496317:Nos2 protein, mouse; D011451:Prostaglandin-Endoperoxide Synthases; C007005:carprofen; D010653:Phenylbutazone; D003002:Clonixin