부산대학교 도서관

To link to full-text access for this article, visit this link: http://dx.doi.org/10.1016/j.intimp.2005.08.017 Byline: Masayasu Iwase, Sayaka Takaoka, Makiko Uchida, Gen Kondo, Hitoshi Watanabe, Masaru Ohashi, Masao Nagumo Keywords: Acute inflammation; Apoptosis; Cyclooxygenase-2 inhibitor; Cytokines; Fas; Neutrophils Abstract: Inflammatory stimuli, such as cytokines, can induce cyclooxygenase-2 (COX-2) expression in neutrophils. Selective, anti-inflammatory COX-2 inhibitors have been developed for patients with acute inflammatory diseases. Recent work has shown that selective COX-2 inhibitors interfere with tumor cell growth. The purpose of this study was to examine the capability of selective COX-2 inhibitors on Fas-mediated apoptosis in cytokine-stimulated neutrophils. Tumor necrosis factor-[alpha] (TNF-[alpha]) and granulocyte-macrophage colony-stimulating factor (GM-CSF) enhanced prostaglandin E.sub.2 (PGE.sub.2) release through the induction of COX-2 in neutrophils. This effect was not seen with either interleukin (IL)-1[beta] or IL-8. TNF-[alpha]-and GM-CSF-induced PGE.sub.2 release was blocked by the addition of the selective COX-2 inhibitor, N-(2-cyclohexyloxy-4-nitrophenyl)-methanesulfonamide (NS-398; 1 [mu]M). GM-CSF, IL-1[beta] and IL-8 suppressed Fas-mediated apoptosis in neutrophils; however, this effect was not seen with TNF-[alpha]. The anti-apoptotic effect of cytokines on Fas-mediated neutrophil apoptosis was attenuated by the addition of NS-398 (100 [mu]M). These results suggest that NS-398 operates via two distinct mechanisms for regulating apoptosis and COX-2 activation in neutrophils. This distinction is indicated by the difference in concentration of NS-398 required for acceleration of Fas-mediated neutrophil apoptosis, and the inhibition of PGE.sub.2 synthesis. Moreover, NS-398 suppressed the anti-apoptotic activity of IL-8 and IL-1[beta], but did not induce COX-2; therefore, the pro-apoptotic mechanism of the selective COX-2 inhibitor may be unrelated to COX-2 activity. Thus, a selective COX-2 inhibitor may contribute to the reduction of acute inflammation through the enhancement of neutrophil apoptosis. Author Affiliation: Department of Oral and Maxillofacial Surgery, Showa University School of Dentistry, 2-1-1, Kitasenzoku, Ota-ku, Tokyo, 145-8515, Japan Article History: Received 9 May 2005; Revised 20 June 2005; Accepted 19 August 2005