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Cutting Edge: A Critical Role of Nitrogen Oxide in Preventing Inflammation upon Apoptotic Cell Clearance¹

Department of Biomolecular Science, Faculty of Science, Toho University, Funabashi, Chiba, Japan

Apoptotic cells are removed by phagocytes without causing inflammation. It remains largely unresolved whether anti-inflammatory mediators prevent neutrophil infiltration upon apoptotic cell clearance in vivo. In this study, we showed that, upon induction of apoptosis in the thymus by x-ray, inducible NO synthase knockout (KO) mice exhibited higher levels of neutrophil infiltration and production of MIP-2 and keratinocyte-derived chemokine (KC) in the thymus than wild-type (WT) mice. Furthermore, administration of N^G-nitro-L-arginine methyl ester, an inhibitor of NO synthase, to x-irradiated WT mice increased the level of neutrophil infiltration to that of KO mice by the augmentation of MIP-2 and KC production. Additionally, thymic macrophages isolated from x-irradiated KO mice produced more MIP-2 and KC than those from WT mice. Thus, although apoptosis is believed to be noninflammatory, this is actually achieved by the production of immunosuppressive signals such as NO that counteract proinflammatory chemokines such as MIP-2 and KC.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This study was supported in part by a grant from the Japan Science Society (to T.S.).

² Address correspondence and reprint requests to Dr. Yoshiro Kobayashi, Division of Molecular Medicine. Department of Biomolecular Science, Faculty of Science, Toho University, 2-2-1 Miyama, Funabashi, Chiba 274-8510, Japan. E-mail address: yoshiro{at}biomol.sci.toho-u.ac.jp

³ Abbreviations used in this paper: iNOS, inducible NO synthase; Gy, gray; KC, keratinocyte-derived chemokine; KO, knockout; L-NAME, N^G-nitro-L-arginine methyl ester; PM, peritoneal resident macrophage; TM, thymic macrophage; WT, wild type.