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J. Biol. Chem., Vol. 281, Issue 26, 17736-17742, June 30, 2006

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Phosphoinositide 3-Kinase in Nitric Oxide Synthesis in Macrophage

CRITICAL DIMERIZATION OF INDUCIBLE NITRIC-OXIDE SYNTHASE^*

Kouhei Sakai, Harumi Suzuki¹, Hiroyo Oda, Takaaki Akaike, Yoshinao Azuma, Tomoyuki Murakami^¶, Kazuro Sugi^¶, Takehito Ito^||, Hiroshi Ichinose^||, Shigeo Koyasu^**, and Mutsunori Shirai

From the Department of Microbiology and Immunology, Yamaguchi University School of Medicine, Minami-Kogushi, Ube-shi, Yamaguchi-Ken, 755-8505, Japan, the Department of Microbiology, Graduate School of Medical Sciences, Kumamoto University, Kumamoto 860-8556, Japan, the ^¶Department of Clinical Research, National Sanyou Hospital, Yamaguchi 755-0241, Japan, the ^||Department of Life Science, Graduate School of Bioscience and Biotechnology, Tokyo Institute of Technology, Nagatsuta-cho, Midori-ku, Yokohama 226-8501, Japan, and the ^**Department of Microbiology and Immunology, Keio University School of Medicine, Shinanomachi, Shinjuku-ku, Tokyo 160-8582, Japan

Phosphoinositide 3-kinase (PI3K) has important functions in various biological systems, including immune response. Although the role of PI3K in signaling by antigen-specific receptors of the adaptive immune system has been extensively studied, less is known about the function of PI3K in innate immunity. In the present study, we demonstrate that macrophages deficient for PI3K (p85 regulatory subunit) are impaired in nitric oxide (NO) production upon lipopolysaccharide and interferon- stimulation and thus vulnerable for intracellular bacterial infection such as Chlamydophila pneumoniae. Although expression of inducible nitric-oxide synthase (iNOS) is induced normally in PI3K-deficient macrophages, dimer formation of iNOS protein is significantly impaired. The amount of intracellular tetrahydrobiopterin, a critical stabilizing cofactor for iNOS dimerization, is decreased in the absence of PI3K. In addition, induction of GTP cyclohydrolase 1, a rate-limiting enzyme for biosynthesis of tetrahydrobiopterin, is greatly reduced. Our current results demonstrate a critical role of class IA type PI3K in the bactericidal activity of macrophages by regulating their NO production through GTP cyclohydrolase 1 induction.

Received for publication, February 28, 2006 , and in revised form, April 21, 2006.

^* This work was supported by a Grant-in-aid for Scientific Research on Priority Areas (13037028, 13670322) from the Japan Society for the Promotion of Science and JSPS-RETE00L0141. 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 To whom correspondence should be addressed: Dept. of Microbiology and Immunology, Yamaguchi University School of Medicine, 1-1-1, Minami-Kogushi, Ube-shi, Yamaguchi-Ken, 755-8505, Japan. Tel.: 81-836-22-2227; Fax: 81-836-22-2415; E-mail: suzukih{at}yamaguchi-u.ac.jp.

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