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J. Biol. Chem., Vol. 276, Issue 19, 16555-16560, May 11, 2001
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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
Distinct Signaling Pathways for MCP-1-dependent
Integrin Activation and Chemotaxis*
,
1 integrin-dependent, but not
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.
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.
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