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J. Biol. Chem., Vol. 283, Issue 8, 4643-4651, February 22, 2008

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Monocyte Chemoattractant Protein-1 Expression Is Enhanced by Granulocyte-Macrophage Colony-stimulating Factor via Jak2-Stat5 Signaling and Inhibited by Atorvastatin in Human Monocytic U937 Cells^*

Akihide Tanimoto¹, Yoshitaka Murata, Ke-Yong Wang, Masato Tsutsui^¶, Kimitoshi Kohno^||, and Yasuyuki Sasaguri

From the Department of Pathology and Cell Biology, ^¶Department of Pharmacology, and ^||Department of Molecular Biology, School of Medicine, University of Occupational and Environmental Health, 1-1 Iseigaoka, Yahatanishi-ku, Kitakyushu 807-8555, Japan and Kyurin Omtest Laboratory Department, Kyurin Corp., Takanosu 1-8-8, Yahatanishi-ku, Kitakyushu 806-0046, Japan

The proinflammatory cytokine granulocyte-macrophage colony-stimulating factor (GM-CSF) is expressed in inflammatory and atherosclerotic lesions. GM-CSF is known to enhance monocytic expression of monocyte chemoattractant protein-1 (MCP-1). However, the molecular mechanism(s) by which GM-CSF up-regulates the MCP-1 expression remains to be clarified. Thus, in this study, we examined our hypothesis that GM-CSF up-regulates the MCP-1 expression via Jak2-Stat5 signaling pathway. In human monocytic cell line U937, GM-CSF increased MCP-1 expression in protein and mRNA levels. Furthermore, analysis of the GM-CSF promoter element revealed that the STAT5 (signal transducer and activator of transcription-5) transcription factor binding site, located between –152 and –144 upstream of the transcription start site, as well as Janus kinase-2-mediated Stat5 activation were necessary for the GM-CSF-induced transcriptional up-regulation of the MCP-1 gene. This GM-CSF-induced MCP-1 expression, measured as both protein and mRNA levels, was down-regulated by atorvastatin, a 3-hydroxy-3-methylglutaryl-CoA reductase inhibitor. However, this decrease in MCP-1 expression was not at the transcriptional level of MCP-1 gene but rather at the level of the stability of MCP-1 mRNA. These results indicate that GM-CSF regulates MCP-1 expression via Janus kinase-2-Stat5 pathway and by a novel regulatory mechanism of statins to reduce inflammatory reactions by down-regulating the expression of monocytic MCP-1, which promotes atherogenesis.

Received for publication, October 26, 2007 , and in revised form, December 12, 2007.

^* This work was supported in part by a grant from the Smoking Research Foundation (to A. T.) and from the Nation Wide Efforts to Standardize Diagnostic and Therapeutic Definition of Vascular Disease of the DVD Research Group, Tokyo, Japan (to Y. S. and A. T.). 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 Pathology and Cell Biology, School of Medicine, University of Occupational and Environmental Health, 1-1 Iseigaoka, Yahatanishi, Kitakyushu 807-8555, Japan. Tel.: 81-93-691-7240; Fax: 81-93-603-8518; E-mail: aki{at}med.uoeh-u.ac.jp.

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