title: Increase of cyclooxygenase-2 expression by interleukin 15 in rheumatoid synoviocytes.
abstract: OBJECTIVE
  To determine the effect of interleukin 15 (IL-15) on cyclooxygenase-2 (COX-2) expression in rheumatoid synoviocytes.
  
  
  METHODS
  Fibroblast-like synoviocytes (FLS) were prepared from the synovial tissues of patients with rheumatoid arthritis (RA) and cultured in the presence of IL-15. Levels of COX-2 mRNA and protein expression were determined by reverse transcription-polymerase chain reaction and Western blot, respectively. ELISA was used to measure concentrations of IL-1beta, tumor necrosis factor-a (TNF-a), and prostaglandin E2 (PGE2) in the culture supernatants.
  
  
  RESULTS
  IL-15 dose-dependently increased COX-2 mRNA and protein expression in FLS, but not the COX-1 mRNA level. Both IL-1beta and TNF-a upregulated COX-2 mRNA comparably to IL-15, but neither IL-2 nor interferon-g had any effect on the COX-2 mRNA level. Treatment with anti-IL-1beta or anti-TNF-a antibodies partially reduced the IL-15-stimulated COX-2 mRNA expression, suggesting that these cytokines may take part in modulating COX-2 by IL-15. Dexamethasone and pyrolidine dithiocarbamate, but not curcumin, completely blocked the IL-15-induced upregulation of COX-2 mRNA. A gel mobility shift assay revealed that nuclear factor-kB (NF-kB) was one of the major signal molecules to mediate IL-15-induced COX-2 upregulation. The increase of COX-2 by IL-15 is PGE2-dependent because exogenous PGE2 reversed the suppressive effect of NS-398, a selective COX-2 inhibitor, on COX-2 mRNA and protein expression.
  
  
  CONCLUSIONS
  This study confirms the effect of IL-15 on upregulation of COX-2 in a PGE2-dependent manner. The activation of NF-kB bound to the COX-2 promoter appears to be a downstream target of IL-15 stimulation in FLS, exerted either directly or through the increase in IL-1beta and TNF-a production.
authors.affiliation: Department of Internal Medicine, Division of Rheumatology, Catholic University of Korea, Seoul, Korea.
authors.forename: So-Youn
authors.initials: SY
authors.lastname: Min
authors.forename: Sue-Yun
authors.initials: SY
authors.lastname: Hwang
authors.forename: Young-Ok
authors.initials: YO
authors.lastname: Jung
authors.forename: Jinyoung
authors.initials: J
authors.lastname: Jeong
authors.forename: Sung-Hwan
authors.initials: SH
authors.lastname: Park
authors.forename: Chul-Soo
authors.initials: CS
authors.lastname: Cho
authors.forename: Ho-Youn
authors.initials: HY
authors.lastname: Kim
authors.forename: Wan-Uk
authors.initials: WU
authors.lastname: Kim
mesh_terms: D019138:Antibodies, Blocking / Q000494:pharmacology; D001172:Arthritis, Rheumatoid / Q000201:enzymology*; D002478:Cells, Cultured; D017077:Culture Media, Conditioned / Q000737:chemistry; D051546:Cyclooxygenase 2; D003907:Dexamethasone / Q000494:pharmacology; D015232:Dinoprostone / Q000096:biosynthesis; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D007375:Interleukin-1 / Q000096:biosynthesis / Q000276:immunology / Q000494:pharmacology; D019409:Interleukin-15 / Q000494:pharmacology*; D007527:Isoenzymes / Q000096:biosynthesis* / Q000235:genetics; D008297:Male; D008565:Membrane Proteins; D008875:Middle Aged; D016328:NF-kappa B / Q000378:metabolism; D011392:Proline / Q000031:analogs & derivatives* / Q000494:pharmacology; D011451:Prostaglandin-Endoperoxide Synthases / Q000096:biosynthesis* / Q000235:genetics; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D013583:Synovial Membrane / Q000187:drug effects / Q000201:enzymology*; D013859:Thiocarbamates / Q000494:pharmacology; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis / Q000276:immunology / Q000494:pharmacology; D015854:Up-Regulation
chemical_list: D019138:Antibodies, Blocking; D017077:Culture Media, Conditioned; D007375:Interleukin-1; D019409:Interleukin-15; D007527:Isoenzymes; D008565:Membrane Proteins; D016328:NF-kappa B; D012333:RNA, Messenger; D013859:Thiocarbamates; D014409:Tumor Necrosis Factor-alpha; C066229:prolinedithiocarbamate; D003907:Dexamethasone; D011392:Proline; D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human; D011451:Prostaglandin-Endoperoxide Synthases; D015232:Dinoprostone