Novel effects of the cyclooxygenase-2-selective inhibitor NS-398 on IL-1β-induced cyclooxygenase-2 and IL-8 expression in human ovarian granulosa cells.
Ovulation is a critical inflammation-like event that is central to ovarian physiology. IL-1β is an immediate early pro-inflammatory cytokine that regulates production of several other inflammatory mediators, such as cyclooxygenase 2 (COX)-2 and IL-8. NS-398 is a selective inhibitor of COX-2 bioactivity and thus this drug is able to mitigate the COX-2-mediated production of downstream prostaglandins and the subsequent inflammatory response. Here we have investigated the action of NS-398 using a human ovarian granulosa cell line, KGN, by exploring IL-1β-regulated COX-2 and IL-8 expression. First, NS-398, instead of reducing inflammation, appeared to further enhance IL-1β-mediated COX-2 and IL-8 production. Using selective inhibitors targeting various signaling molecules, MAPK and NF-κB pathways both seemed to be involved in the impact of NS-398 on IL-1β-induced COX-2 and IL-8 expression. NS-398 also promoted IL-1β-mediated NF-κB p65 nuclear translocation but had no effect on IL-1β-activated MAPK phosphorylation. Flow cytometry analysis demonstrated that NS-398, in combination with IL-1β, significantly enhanced cell cycle progression involving IL-8. Our findings demonstrate a clear pro-inflammatory function for NS-398 in the IL-1β-mediated inflammatory response of granulosa cells, at least in part, owing to its augmenting effect on the IL-1β-induced activation of NF-κB.
Department of Physiology, School of Medicine, National Yang-Ming University, Taipei, Taiwan.
Hui-Ling
HL
Ou
Department of Obstetrics and Gynecology, Cheng Hsin General Hospital, Taipei, Taiwan.
David
D
Sun
Department of Internal Medicine, Taichung Veterans General Hospital, Taichung, Taiwan.
Yen-Chun
YC
Peng
Department of Physiology, School of Medicine, National Yang-Ming University, Taipei, Taiwan ylwu@ym.edu.tw.
Yuh-Lin
YL
Wu
D002460:Cell Line; D051546:Cyclooxygenase 2 / Q000235:genetics / Q000378:metabolism*; D052246:Cyclooxygenase 2 Inhibitors / Q000494:pharmacology*; D015232:Dinoprostone / Q000378:metabolism; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects; D006107:Granulosa Cells / Q000187:drug effects* / Q000276:immunology; D006801:Humans; D007249:Inflammation / Q000276:immunology*; D053583:Interleukin-1beta / Q000276:immunology; D016209:Interleukin-8 / Q000235:genetics / Q000378:metabolism*; D016328:NF-kappa B / Q000378:metabolism; D009578:Nitrobenzenes / Q000494:pharmacology*; D010060:Ovulation / Q000276:immunology*; D015398:Signal Transduction / Q000187:drug effects; D013449:Sulfonamides / Q000494:pharmacology*
D052246:Cyclooxygenase 2 Inhibitors; D053583:Interleukin-1beta; D016209:Interleukin-8; D016328:NF-kappa B; D009578:Nitrobenzenes; D013449:Sulfonamides; C080955:N-(2-cyclohexyloxy-4-nitrophenyl)methanesulfonamide; C077623:Ptgs2 protein, mouse; D051546:Cyclooxygenase 2; D015232:Dinoprostone
Cyclooxygenase-2; NS-398; granulosa cells; inflammation; interleukin-8