Increase of Cyclooxygenase-2 Expression by Interleukin 15 in Rheumatoid Synoviocytes

SO-YOUN MIN, SUE-YUN HWANG, YOUNG-OK JUNG, JINYOUNG JEONG, SUNG-HWAN PARK, CHUL-SOO CHO, HO-YOUN KIM, and WAN-UK KIM

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-1ß, 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-1ß 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-1ß 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.

Conclusion. 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-1ß and TNF-a production. (J Rheumatol 2004;31:875-83)

Key Indexing Terms:

INTERLEUKIN 15
SYNOVIOCYTES
CYCLOOXYGENASE-2 NUCLEAR FACTOR-kB

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From the Department of Internal Medicine, Division of Rheumatology; and Department of Orthopedic Surgery, Center for Rheumatic Diseases, Catholic University of Korea, Seoul, Korea.

Supported by a grant from the Ministry of Health and Welfare of the Republic of Korea (No. 03-PJ1-PG10-20500-0021).

S-Y. Min, PhD; S-Y. Hwang, PhD, Rheumatism Research Center, Catholic Institutes of Medical Science, Catholic University of Korea, Seoul; Y-O. Jung, MD, Division of Rheumatology, Department of Internal Medicine, Hallym University Medical College, Seoul; J. Jeong, MD, Department of Orthopedic Surgery; W-U. Kim, MD, Division of Rheumatology, Department of Internal Medicine, School of Medicine, Catholic University of Korea, St. Vincent's Hospital, Suwon; S-H. Park, MD; C-S. Cho, MD; H-Y. Kim, MD, Division of Rheumatology, Department of Internal Medicine, School of Medicine, Catholic University of Korea, Kang-Nam St. Mary's Hospital.

Address reprint requests to Dr. W-U. Kim, Division of Rheumatology, Department of Internal Medicine, School of Medicine, Catholic University of Korea, St. Vincent's Hospital, 93 Chi-Dong, Suwon 442-060, South Korea. E-mail: wan725@catholic.ac.kr

Submitted March 21, 2003; revision accepted October 1, 2003.

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