title: Induction of apoptosis in rheumatoid synovial fibroblasts by celecoxib, but not by other selective cyclooxygenase 2 inhibitors.
abstract: OBJECTIVE
  Selective cyclooxygenase 2 (COX-2) inhibitors are now being used as antiinflammatory agents that cause fewer gastrointestinal complications, compared with other antiinflammatory drugs, in patients with rheumatoid arthritis (RA). This study was undertaken to investigate whether selective COX-2 inhibitors could induce apoptosis of RA synovial fibroblasts (RASFs).
  
  
  METHODS
  RASFs were exposed to selective COX-2 inhibitors, i.e., celecoxib, etodolac, meloxicam, nimesulide, N-[2-(cyclohexyloxyl)-4-nitrophenyl]-methanesulfonamide, and rofecoxib, under various conditions. Cell proliferation and cell viability were assessed by incorporation of 5-bromo-2'-deoxyuridine and by the 2-(4-iodophenyl)-3-(4-nitrophenyl)-5-(2,4-disulfophenyl)-2H-tetrazolium monosodium salt assay, respectively. Apoptosis was detected by identifying DNA fragmentation. Activation of peroxisome proliferator-activated receptor gamma (PPARgamma) was measured by the luciferase reporter gene assay with a PPAR response element-driven luciferase reporter plasmid and a PPARgamma expression plasmid.
  
  
  RESULTS
  Celecoxib strongly inhibited the proliferation of RASFs, whereas other selective COX-2 inhibitors had little or no effect. In addition, celecoxib reduced the viability of RASFs by induction of apoptosis, in a concentration-dependent manner. This action was abolished by addition of caspase inhibitors. Interleukin-1beta had a weak enhancing effect on celecoxib-induced apoptosis in RASFs. In contrast, other selective COX-2 inhibitors at concentrations up to 100 microM did not induce apoptosis of RASFs. Indomethacin, a nonselective COX inhibitor, activated PPARgamma transcription, while celecoxib did not.
  
  
  CONCLUSIONS
  Celecoxib suppressed the proliferation of RASFs by COX-2-independent and PPARgamma-independent induction of apoptosis. Although the mechanism involved remains unclear, celecoxib may have not only antiinflammatory activity, but also a disease-modifying effect on rheumatoid synovial proliferation.
authors.affiliation: St. Marianna University School of Medicine, Kawasaki, Japan.
authors.forename: Natsuko
authors.initials: N
authors.lastname: Kusunoki
authors.forename: Ryuta
authors.initials: R
authors.lastname: Yamazaki
authors.forename: Shinichi
authors.initials: S
authors.lastname: Kawai
mesh_terms: D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology; D017209:Apoptosis; D001172:Arthritis, Rheumatoid / Q000503:physiopathology*; D000068579:Celecoxib; D002455:Cell Division / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D051546:Cyclooxygenase 2; D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology*; D015232:Dinoprostone / Q000096:biosynthesis; D005347:Fibroblasts / Q000187:drug effects / Q000502:physiology*; D006801:Humans; D007527:Isoenzymes / Q000037:antagonists & inhibitors*; D008565:Membrane Proteins; D011451:Prostaglandin-Endoperoxide Synthases; D011720:Pyrazoles; D018160:Receptors, Cytoplasmic and Nuclear / Q000502:physiology; D013449:Sulfonamides / Q000494:pharmacology*; D013583:Synovial Membrane / Q000503:physiopathology*; D014157:Transcription Factors / Q000502:physiology
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors; D007527:Isoenzymes; D008565:Membrane Proteins; D011720:Pyrazoles; D018160:Receptors, Cytoplasmic and Nuclear; D013449:Sulfonamides; D014157:Transcription Factors; D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human; D011451:Prostaglandin-Endoperoxide Synthases; D000068579:Celecoxib; D015232:Dinoprostone