title: Accelerative effect of a selective cyclooxygenase-2 inhibitor on Fas-mediated apoptosis in human 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 E2 (PGE2) release through the induction of COX-2 in neutrophils. This effect was not seen with either interleukin (IL)-1beta or IL-8. TNF-alpha-and GM-CSF-induced PGE2 release was blocked by the addition of the selective COX-2 inhibitor, N-(2-cyclohexyloxy-4-nitrophenyl)-methanesulfonamide (NS-398; 1 microM). GM-CSF, IL-1beta 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 microM). 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 PGE2 synthesis. Moreover, NS-398 suppressed the anti-apoptotic activity of IL-8 and IL-1beta, 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.
authors.affiliation: Department of Oral and Maxillofacial Surgery, Showa University School of Dentistry, 2-1-1, Kitasenzoku, Ota-ku, Tokyo, 145-8515, Japan. iwase@senzoku.showa-u.ac.jp
authors.forename: Masayasu
authors.initials: M
authors.lastname: Iwase
authors.forename: Sayaka
authors.initials: S
authors.lastname: Takaoka
authors.forename: Makiko
authors.initials: M
authors.lastname: Uchida
authors.forename: Gen
authors.initials: G
authors.lastname: Kondo
authors.forename: Hitoshi
authors.initials: H
authors.lastname: Watanabe
authors.forename: Masaru
authors.initials: M
authors.lastname: Ohashi
authors.forename: Masao
authors.initials: M
authors.lastname: Nagumo
mesh_terms: D017209:Apoptosis / Q000187:drug effects*; D051546:Cyclooxygenase 2 / Q000096:biosynthesis / Q000235:genetics; D052246:Cyclooxygenase 2 Inhibitors / Q000494:pharmacology*; D016207:Cytokines / Q000502:physiology; D015232:Dinoprostone / Q000378:metabolism; D004790:Enzyme Induction / Q000187:drug effects; D006801:Humans; D009504:Neutrophils / Q000187:drug effects* / Q000201:enzymology; D009578:Nitrobenzenes / Q000494:pharmacology*; D012333:RNA, Messenger / Q000378:metabolism; D013449:Sulfonamides / Q000494:pharmacology*; D019014:fas Receptor / Q000502:physiology*
chemical_list: D052246:Cyclooxygenase 2 Inhibitors; D016207:Cytokines; C491901:FAS protein, human; D009578:Nitrobenzenes; D012333:RNA, Messenger; D013449:Sulfonamides; D019014:fas Receptor; C080955:N-(2-cyclohexyloxy-4-nitrophenyl)methanesulfonamide; D051546:Cyclooxygenase 2; D015232:Dinoprostone