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J Biol Chem, Vol. 275, Issue 8, 5810-5816, February 25, 2000

Sites of Action of Protein Kinase C and Phosphatidylinositol 3-Kinase Are Distinct in Oxidized Low Density Lipoprotein-induced Macrophage Proliferation^*

Takeshi Biwa, Masakazu Sakai, Takeshi Matsumura, Shozo Kobori, Kengo Kaneko, Akira Miyazaki^§, Hideki Hakamata^§, Seikoh Horiuchi^§¶, and Motoaki Shichiri

From the Departments of  Metabolic Medicine and ^§ Biochemistry, Kumamoto University School of Medicine, Honjo 1-1-1, Kumamoto 860-8556, Japan

Oxidized low density lipoprotein (Ox-LDL) can induce macrophage proliferation in vitro. To explore the mechanisms involved in this process, we reported that activation of protein kinase C (PKC) is involved in its signaling pathway (Matsumura, T., Sakai, M., Kobori, S., Biwa, T., Takemura, T., Matsuda, H., Hakamata, H., Horiuchi, S., and Shichiri, M. (1997) Arterioscler. Thromb. Vasc. Biol. 17, 3013-3020) and that expression of granulocyte/macrophage colony-stimulating factor (GM-CSF) and its subsequent release in the culture medium are important (Biwa, T., Hakamata, H., Sakai, M., Miyazaki, A., Suzuki, H., Kodama, T., Shichiri, M., and Horiuchi, S. (1998) J. Biol. Chem. 273, 28305-28313). However, a recent study also demonstrated the involvement of phosphatidylinositol 3-kinase (PI3K) in this process. In the present study, we investigated the role of PKC and PI3K in Ox-LDL-induced macrophage proliferation. Ox-LDL-induced macrophage proliferation was inhibited by 90% by a PKC inhibitor, calphostin C, and 50% by a PI3K inhibitor, wortmannin. Ox-LDL-induced expression of GM-CSF and its subsequent release were inhibited by calphostin C but not by wortmannin, whereas recombinant GM-CSF-induced macrophage proliferation was inhibited by wortmannin by 50% but not by calphostin C. Ox-LDL activated PI3K at two time points (10 min and 4 h), and the activation at the second but not first point was significantly inhibited by calphostin C and anti-GM-CSF antibody. Our results suggest that PKC plays a role upstream in the signaling pathway to GM-CSF induction, whereas PI3K is involved, at least in part, downstream in the signaling pathway after GM-CSF induction.

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^* This work was supported in part by Grant-in-aid for Scientific Research on Priority Area A02 and Grants-in-aid for Scientific Research 10671077 and 11557081 from the Ministry of Education, Science, Sports and Culture and by a grant from Sagawa Science Foundation.The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

^¶ To whom correspondence should be addressed. Tel./Fax: 81-96-364-6940; E-mail: horiuchi@gpo.kumamoto-u.ac.jp.

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Copyright © 2000 by The American Society for Biochemistry and Molecular Biology, Inc.

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