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J. Biol. Chem., Vol. 283, Issue 15, 9692-9703, April 11, 2008

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Prostaglandin E Receptor Type 4-associated Protein Interacts Directly with NF-B1 and Attenuates Macrophage Activation^*

From the Cardiovascular Division, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02115

Macrophage activation participates pivotally in the pathophysiology of chronic inflammatory diseases, including atherosclerosis. Through the receptor EP4, prostaglandin E₂ (PGE₂) exerts an anti-inflammatory action in macrophages, suppressing stimulus-induced expression of certain proinflammatory genes, including chemokines. We recently identified a novel EP4 receptor-associated protein (EPRAP), whose function in PGE₂-mediated anti-inflammation remains undefined. Here we demonstrate that PGE₂ pretreatment selectively inhibits lipopolysaccharide (LPS)-induced nuclear factor B1 (NF-B1) p105 phosphorylation and degradation in mouse bone marrow-derived macrophages through EP4-dependent mechanisms. Similarly, directed EPRAP expression in RAW264.7 cells suppresses LPS-induced p105 phosphorylation and degradation, and subsequent activation of mitogen-activated protein kinase kinase 1/2. Forced expression of EPRAP also inhibits NF-B activation induced by various proinflammatory stimuli in a concentration-dependent manner. In co-transfected cells, EPRAP, which contains multiple ankyrin repeat motifs, directly interacts with NF-B1 p105/p50 and forms a complex with EP4. In EP4-overexpressing cells, PGE₂ enhances the protective action of EPRAP against stimulus-induced p105 phosphorylation, whereas EPRAP silencing in RAW264.7 cells impairs the inhibitory effect of PGE₂-EP4 signaling on LPS-induced p105 phosphorylation. Additionally, EPRAP knockdown as well as deficiency of NF-B1 in macrophages attenuates the inhibitory effect of PGE₂ on LPS-induced MIP-1β production. Thus, PGE₂-EP4 signaling augments NF-B1 p105 protein stability through EPRAP after proinflammatory stimulation, limiting macrophage activation.

Received for publication, November 27, 2007 , and in revised form, February 6, 2008.

^* This work was supported by grants from the Donald W. Reynolds Foundation and NHLBI, National Institutes of Health, Grant HL-34636 (to P. L.). The authors have no conflicting financial interests to disclose. 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.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Table S1.

¹ Supported by an American Heart Association Scientist Development grant.

² To whom correspondence should be addressed: 77 Ave. Louis Pasteur, Boston, MA 02115. Tel.: 617-732-8086; Fax: 617-264-5111; E-mail: plibby{at}rics.bwh.harvard.edu.

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