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J. Biol. Chem. 276 (19): 16555-16560

© 2001 by The American Society for Biochemistry and Molecular Biology, Inc.

Distinct Signaling Pathways for MCP-1-dependent Integrin Activation and Chemotaxis*

Noboru Ashida, Hidenori AraiDagger , Masahide Yamasaki, and Toru Kita

From the Department of Geriatric Medicine, Kyoto University Graduate School of Medicine, Kyoto, 606-8507, Japan

Transmigration of monocytes to the subendothelial space is the initial step of atherosclerotic plaque formation and inflammation. Integrin activation and chemotaxis are two important functions involved in monocyte transmigration. To delineate the signaling cascades leading to integrin activation and chemotaxis by monocyte chemoattractant protein-1 (MCP-1), we have investigated the roles of MAPK and Rho GTPases in THP-1 cells, a monocytic cell line. MCP-1 stimulated beta 1 integrin-dependent, but not beta 2 integrin-dependent cell adhesion in a time-dependent manner. MCP-1-mediated cell adhesion was inhibited by a MEK inhibitor but not by a p38-MAPK inhibitor. In contrast, MCP-1-mediated chemotaxis was inhibited by the p38-MAPK inhibitor but not by the MEK inhibitor. The inhibitor of Rho GTPase, C3 exoenzyme, and a Rho kinase inhibitor abrogated MCP-1-dependent chemotaxis but not integrin-dependent cell adhesion. Further, C3 exoenzyme and the Rho kinase inhibitor blocked MCP-1-dependent p38-MAPK activation. These data indicate that ERK is responsible for integrin activation, that p38-MAPK and Rho are responsible for chemotaxis mediated by MCP-1, and that Rho and the Rho kinase are upstream of p38-MAPK in MCP-1-mediated signaling. This study demonstrates that two distinct MAPKs regulate two dependent signaling cascades leading to integrin activation and chemotaxis induced by MCP-1 in THP-1 cells.

* This study was supported by grants-in-aid from the Ministry of Education, Science, Sports, and Culture of Japan; International Scientific Research Program grants from the Japanese Ministry of Education, Science, Sports, and Culture; Center of Excellence grants from the Japanese Ministry of Education, Science, Sports, and Culture; and a research grant for health sciences from the Japanese Ministry of Health and Welfare.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.

Dagger To whom the correspondence should be addressed: Dept. of Geriatric Medicine, Kyoto University Graduate School of Medicine, 54 Kawahara-cho, Shogoin, Sakyo-ku, Kyoto, 606-8507, Japan. Tel.: 81-75-751-3463; Fax: 81-75-751-3463; E-mail: harai@kuhp.kyoto-u.ac.jp.

Copyright © 2001 by The American Society for Biochemistry and Molecular Biology, Inc.

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