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J. Biol. Chem., Vol. 281, Issue 42, 31212-31221, October 20, 2006

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Interferon--inducible Protein (IP)-10 mRNA Stabilized by RNA-binding Proteins in Monocytes Treated with S100b^*

Narkunaraja Shanmugam, Richard M. Ransohoff, and Rama Natarajan¹

From the Gonda Diabetes Research Center, Beckman Research Institute of City of Hope, Duarte, California 91010 and the Lerner Research Institute, Cleveland, Ohio 44195

Chemokines mediate the recruitment and activation of blood monocyte/macrophages and lymphocytes to sites of inflammation. Expression of the chemokine IP-10 (interferon--inducible protein) has been documented in several inflammatory and autoimmune disorders including type 1 diabetes. However, the mechanism of its expression in monocytes or its functional role in diabetes is not known. Advanced glycation end products acting via their receptor, RAGE, play major roles in diabetic complications. In this study, we observed for the first time that S100b, an inflammatory protein as well as a specific RAGE ligand, significantly increased IP-10 mRNA and protein levels in THP-1 monocytes as well as peripheral blood monocytes. Promoter luciferase assays showed that IP-10 mRNA accumulation by S100b was not via increased transcription. On the other hand, S100b significantly increased IP-10 mRNA half-life and stability. This appeared to be mediated by S100b-induced binding of specific RNA-binding protein(s) to a 3'-untranslated region-responsive region of the IP-10 mRNA. Our results demonstrate for the first time that diabetic stimuli such as RAGE ligands can induce inflammatory gene expression in monocytes via increased message stability.

Received for publication, March 15, 2006 , and in revised form, August 23, 2006.

^* This work was supported by National Institutes of Health Grants RO1 DK065073 (to R. N.) and RO1 NS32151 (to R. M. R.), funds from the Juvenile Diabetes Research Foundation (to R. N.), and in part by General Clinical Research Center Grant NCRR MO1RR00043 from the National Center for Research Resources (awarded to the City of Hope). 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 Diabetes, Beckman Research Institute of City of Hope, 1500 East Duarte Rd., Duarte, CA 91010. Tel.: 626-256-4673 (ext. 62289); Fax: 626-301-8136; E-mail: rnatarajan{at}coh.org.

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