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Inflammatory Mechanisms of Atherosclerosis


Pro-inflammatory pathways participate in the pathogenesis of atherosclerosis and other vascular diseases. However, the role of endogenous anti-inflammatory pathways in atheroma has received much less attention. We previously described prostaglandin E2 (PGE2)-induced inhibition of smooth muscle cell proliferation. Recent studies using cDNA microarrays screened for genes regulated by PGE2 in LPS-treated human macrophages (MO). PGE2 (50nM) attenuated LPS-induced mRNA and protein expression of chemokines including monocyte chemoattractant protein-1, IL-8, macrophage inflammatory protein (MIP)-1alpha, MIP-1beta, and IFN-inducible protein-10 (IP-10) in cultured human MO. PGE2 also inhibited the TNF-alpha-, IFN-gamma-, and IL-1beta-mediated expression of these chemokines. MO expressed the PGE2 receptor EP4 both in culture and in human atheroma. A selective EP4 antagonist completely reversed PGE2-mediated suppression of MO chemokine production. Thus, our pilot data show that endogenous PGE2 may modulate inflammation during atherogenesis and other inflammatory diseases by suppressing macrophage-derived chemokine production via the EP4 receptor. "Classical" signal transduction pathways of PGE2 such as cAMP/CREB did not appear to mediate EP4R's attenuation of chemokine gene expression, but we have identified a novel interactor of EP4R using the yeast two-hybrid approach we denote EP4R-Associated Protein (EPRAP). We now propose to test a series of concerted hypotheses regarding the functions in vitro and in vivo of the novel endogenous anti-inflammatory pathway we have uncovered during the last funding period. Specific Aims: 1. We will test the hypothesis that loss of EP4 function will limit chemokine gene expression and other inflammatory functions in mononuclear phagocytes in vitro. 2. We will test further the hypothesis that an EP4-dependent endogenous anti-inflammatory pathway operates during acute inflammation in vivo. 3. We will test the hypothesis that an EP4-dependent endogenous anti-inflammatory pathway attenuates inflammation during atherogenesis in vivo, as a model of chronic inflammation. 4. We will pursue the intracellular signaling pathways by which EP4 exerts its anti-inflammatory action. 5. We will explore a putative functional role of a novel prostaglandin E2 receptor EP4 interacting protein (EPRAP) in endogenous anti-inflammatory pathways.


Funded by the NIH National Center for Advancing Translational Sciences through its Clinical and Translational Science Awards Program, grant number UL1TR002541.