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J. Biol. Chem., Vol. 282, Issue 14, 10146-10152, April 6, 2007

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A Novel Role for the Glucocorticoid Receptor in the Regulation of Monocyte Chemoattractant Protein-1 mRNA Stability^*

From the Cardiovascular Research Institute, University of Rochester, Rochester, New York 14620

Monocyte chemoattractant protein-1 (MCP-1) plays an important role in attracting monocytes to sites of inflammation and is the dominant mediator of macrophage accumulation in atherosclerotic plaques. We have previously shown that glucocorticoids inhibit the secretion of MCP-1 in arterial smooth muscle cells (SMC) by markedly decreasing MCP-1 mRNA stability. We now report that the destabilization of MCP-1 mRNA is mediated by the glucocorticoid receptor (GR). The GR antagonist, RU486, blocked the effect of the glucocorticoid dexamethasone (Dex) on MCP-1 mRNA stability in SMC culture. Using a previously reported in vitro mRNA gel shift and stability assay, antibodies to the GR blocked the ability of cytoplasmic extracts from Dex-treated SMC to decay MCP-1 mRNA. Recombinant human GR (rhGR) bound in a concentration-dependent manner to in vitro transcribed MCP-1 mRNA, whereas other members of the steroid hormone receptor family did not. Binding of GR to MCP-1 mRNA was specific as it was not found to bind other mRNAs. Immunoprecipitation of GR in extracts from Dex-treated SMC followed by real-time reverse transcription-PCR demonstrated that endogenous GR was bound specifically to MCP-1 mRNA. The addition of exogenous rhGR blocked the ability of extracts from Dex-treated SMC to degrade MCP-1 mRNA, suggesting that exogenous rhGR can compete with an endogenous GR-containing degradative complex. These data suggest a novel role for the GR in binding to and facilitating mRNA degradation. These results provide novel insights into GR function and may provide a new approach to attenuate the inflammatory response mediated by MCP-1.

Received for publication, June 21, 2006 , and in revised form, January 30, 2007.

^* This work was supported by National Institutes of Health Grants, R01 HL77669 and P01 HL77789. 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 Both authors contributed equally to this manuscript.

² To whom correspondence should be addressed: University of Rochester, School of Medicine and Dentistry, 601 Elmwood Ave., Box 679-CVRI, Rochester, NY 14620. Tel.: 585-275-7513; Fax: 585-276-1914; E-mail: mark_taubman{at}urmc.rochester.edu.

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