Increase of cyclooxygenase-2 expression by interleukin 15 in rheumatoid synoviocytes
Min, S-Youn.; Hwang, S-Yun.; Jung, Y-Ok.; Jeong, J.; Park, S-Hwan.; Cho, C-Soo.; Kim, H-Youn.; Kim, W-Uk.
Journal of Rheumatology 31(5): 875-883
2004
ISSN/ISBN: 0315-162X PMID: 15124245 Document Number: 580345
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-alpha (TNF-alpha), 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-alpha upregulated COX-2 mRNA comparably to IL-15, but neither IL-2 nor interferon-gamma had any effect on the COX-2 mRNA level. Treatment with anti-IL-1beta or anti-TNF-alpha 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-kappaB (NF-kappaB) 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. Conclusion. This study confirms the effect of IL-15 on upregulation of COX-2 in a PGE2-dependent manner. The activation of NF-kappaB 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-alpha production.