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J. Biol. Chem., Vol. 283, Issue 4, 1778-1785, January 25, 2008

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p38 Stabilizes Interleukin-6 mRNA via Multiple AU-rich Elements^*

From the Department of Periodontics and Oral Medicine, University of Michigan, Ann Arbor, Michigan 48109-1078

AU-rich elements (AREs) in the 3'-untranslated region (UTR) of unstable mRNA dictate their degradation or mediate translational repression. Cell signaling through p38 MAPK is necessary for post-transcriptional regulation of many pro-inflammatory cytokines. Here, the cis-acting elements of interleukin-6 (IL-6) 3'-UTR mRNA that required p38 signaling for mRNA stability and translation were identified. Using mouse embryonic fibroblasts (MEFs) derived from p38^+/+ and p38^–/– mice, we observed that p38 is obligatory for the IL-1-induced IL-6 biosynthesis. IL-6 mRNA stability is promoted by p38 via 3'-UTR. To understand the mechanism of cis-elements regulated by p38 at post-transcriptional level, truncation of 3'-UTR and the full-length 3'-UTR with individual AUUUA motif mutation placed in gene reporter system was employed. Mutation-based screen performed in p38^+/+ and p38^–/– mouse embryonic fibroblast cells revealed that ARE1, ARE2, and ARE5 in IL-6 3'-UTR were targeted by p38, and truncation-based screen showed that IL-6 3'-UTR-(56–173) was targeted by p38 to stable mRNA. RNA secondary structure analysis indicated that modulated reporter gene expression was consistent with predicted secondary structure changes.

Received for publication, September 10, 2007 , and in revised form, November 21, 2007.

^* This work was supported by Dept. of Defense Grant W81XWH-05-0075 (to K. L. K.). 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 Periodontics and Oral Medicine, University of Michigan, 1011 N. University Ave., Ann Arbor, MI 48109-1078. Tel.: 734-763-7120; Fax: 734-763-5503; E-mail: klkirk{at}umich.edu.

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