Opposite effects of rofecoxib on nuclear factor-kappaB and activating protein-1 activation.
Rofecoxib is a selective cyclooxygenase (COX)-2 inhibitor approved for the treatment of pain and inflammation in rheumatoid and osteoarthritis. Daily doses between 12.5 and 50 mg were found to reduce pain and inflammation, however, without a clear dose-effect relationship. Interestingly, rofecoxib treatment is associated with an unexpected incidence of renal adverse events compared with other COX inhibitors. Here, the effects of rofecoxib on the transcription factors nuclear factor-kappaB (NF-kappaB) and activating protein-1 (AP-1) were analyzed to find out whether transcriptional changes might explain the lack of clear dose dependency and the occurrence of renal side effects. In vitro, rofecoxib dose dependently inhibited DNA binding capacity of NF-kappaB at doses of 10 to 100 microM, whereas the binding activity of AP-1 was considerably increased at 100 microM. In vivo, the anti-inflammatory effect of rofecoxib was equal at 1 and 10 mg/kg, whereas 50 mg/kg caused a significant further reduction of a zymosan-induced paw edema. This was associated with a clear decrease of inducible nitric oxide synthase (iNOS) protein expression in the spinal cord at this dose. At 1 and 10 mg/kg, however, iNOS was increased but COX-2 was decreased. Thus, the expression of proinflammatory proteins was similarly inconsistent as transcription factor regulation. In conclusion, the opposite effects of rofecoxib on AP-1 and NF-kappaB may explain the lack of clear dose dependency with rofecoxib in clinical studies or animal experiments. The effects on AP-1 may possibly affect renal sodium transport because certain renal sodium channels are regulated through AP-1. Transcription factor regulation might therefore influence both wanted and unwanted effects of rofecoxib.
Niederberger
Ellen
E
Pharmazentrum frankfurt, Klinikum der Johann Wolfgang Goethe-Universität Frankfurt, Frankfurt am Main, Germany. e.niederberger@em.uni-frankfurt.de
Tegeder
Irmgard
I
Schäfer
Christine
C
Seegel
Maic
M
Grösch
Sabine
S
Geisslinger
Gerd
G
D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology*; D002478:Cells, Cultured; D004195:Disease Models, Animal; D007249:Inflammation / Q000139:chemically induced / Q000517:prevention & control; D007783:Lactones / Q000494:pharmacology* / Q000627:therapeutic use; D008297:Male; D051379:Mice; D016328:NF-kappa B / Q000378:metabolism*; D011817:Rabbits; D051381:Rats; D017207:Rats, Sprague-Dawley; D013450:Sulfones; D018808:Transcription Factor AP-1 / Q000378:metabolism*; D015054:Zymosan
D000894:Anti-Inflammatory Agents, Non-Steroidal; D007783:Lactones; D016328:NF-kappa B; D013450:Sulfones; D018808:Transcription Factor AP-1; C116926:rofecoxib; D015054:Zymosan