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J. Biol. Chem., Vol. 282, Issue 30, 21776-21785, July 27, 2007

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Inflammatory Signaling Pathways Regulating ApoE Gene Expression in Macrophages^*

Anca V. Gafencu¹, Marius R. Robciuc, Elena Fuior, Vassilis I. Zannis^¶, Dimitris Kardassis, and Maya Simionescu

From the Institute of Cellular Biology and Pathology Nicolae Simionescu, 8 B. P. Hasdeu Street, P. O. B. 35-14, Sect. 5, Bucharest 050568, Romania, the University of Crete Medical School, Heraklion, Crete GB-71110 Greece, and the ^¶Boston University School of Medicine, Boston, Massachusetts 02718

The atheroprotective role of apolipoprotein E (apoE) is well established. During inflammation, expression of apoE in macrophages is reduced leading to enhanced atheromatous plaque development. In the present study, we investigated the signaling pathways involved in the repression of apoE gene expression in response to lipopolysaccharide (LPS) treatment, a condition that mimics the inflammatory stress, in mouse macrophages RAW 264.7. We identified Tpl-2 and MEKK1 as the kinases that are primarily responsible for the down-regulation of apoE promoter activity by LPS. Using a dominant negative form of IB, we established that Tpl-2 and MEKK1 signaling pathways converge to NF-B acting on the apoE core promoter –55/+73. In addition to NF-B activation, LPS also activated c-Jun via its phosphorylation by JNK. The activity of the apoE promoter was repressed by c-Jun, whereas small interference RNA-mediated inhibition of endogenous c-Jun expression reversed the inhibitory effect of Tpl-2 on the apoE promoter. Transfection experiments and DNA binding assays showed that the binding site for c-Jun is in the –55/+73 region of the apoE promoter. Finally, we showed that LPS inhibited apoE gene expression via activation of the Tpl-2/MEK/ERK pathway acting on a different apoE promoter region. In summary, LPS represses apoE gene expression in macrophages via signaling pathways that involve the upstream kinases Tpl-2 and MEKK1, the intermediate mitogen-activated protein kinases ERK and JNK, and the downstream transcription factors AP-1 and NF-B that inhibit the apoE promoter activity via distinct regions.

Received for publication, December 13, 2006 , and in revised form, May 4, 2007.

^* This work was supported by a grant form the Romanian Ministry of Education and Research ("Excellence Research Program: Projects for Young Researchers" to A. G.), a Collaborative NATO Science Grant (to V. Z. and M. S.), and a collaborative grant awarded by the Greek and Romanian Ministries of Research (to A. G. and D. 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: Tel.: 4021-319-4518; Fax: 4021-319-4519; E-mail: anca.gafencu{at}icbp.ro.

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