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

Cardiovascular Division, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, 77 Avenue Louis Pasteur, Boston, MA 02115, USA.
Journal of Biological Chemistry (Impact Factor: 4.57). 05/2008; 283(15):9692-703. DOI: 10.1074/jbc.M709663200
Source: PubMed


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 κB1 (NF-κB1) 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-κB 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-κB1 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-κB1 in macrophages
attenuates the inhibitory effect of PGE2 on LPS-induced MIP-1β production. Thus, PGE2-EP4 signaling augments NF-κB1 p105 protein stability through EPRAP after proinflammatory stimulation, limiting macrophage

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    • "Kabashima et al. [84] reported that edema, inflammatory cell infiltration, and local blood flow were reduced in both EP2 and EP4 null mice. Interestingly, EP4 mediates an anti-inflammatory response in macrophages and does so through an EP4 (but not EP2) interacting protein, EP4 receptor-associated protein (EPRAP); the complex also interacts with NFκB [85]. Whether EPRAP is expressed in other cell types is unknown. "
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    • "Pretreatment of bone marrow-derived macrophages with PGE 2 prior to activation with LPS, results in a transitory attenuation of the early phase of production of chemokines and inflammatory cytokines(Minami et al., 2008). Interestingly, this anti-inflammatory effect is mediated by a novel EP4 receptor associated protein that inhibits LPS induced activation of NFkB(Minami et al., 2008). In the absence of pre-treatment with PGE 2 , we report that activation of EP4 −/− macrophages with LPS results in significant suppression of NF-κB-responsive genes and proteins, and suggesting that macrophage EP-4 may impact atherosclerosis by its effects on inflammatory cytokines such as IL-6 and MCP-1 (Fig. 6). "
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