Abstract 2572: Pro-resolving effects of 15-deoxy-α12,14-prostaglandin J2 through activation of Nrf2-mediated CD36 expression in murine macrophages

Abstract

Abstract The process of resolution of inflammation is actively controlled by a series of endogenous mediators, which activate pro-resovling mechanisms. 15-Deoxy-α12,14-prostaglandin J2 (15d PGJ2), one of the terminal products of cyclooxygenase-2 (COX-2), is an endogenous lipid mediator exerting both anti-inflammatory and pro-resolving effects. Enhanced biosynthesis of 15d-PGJ2 has been suggested to contribute to resolution of inflammation. The phagocytosis of apoptotic neutrophils by macrophages, called effercytosis, is the most important step for complete resolution of inflammation. However, the molecular mechanisms underlying pro-resolving effects of 15d-PGJ2 remain not fully clarified. The phagocytic action of macrophages is known to be mediated by scavenger receptors present on the plasma membrane of these cells. CD36, one of the class B scavenger receptors, is considered to recognize phosphatidylserine on the outer membrane of apoptotic neutrophils, thereby inducing phagocytosis. Recently, NF-E2 related factor 2 (Nrf2) has been reported to be the essential transcription factor involved in the induction of CD36 expression. In the present study, we found that 15d-PGJ2 (1 μM) increased expression and nuclear translocation of Nrf2 in murine macrophage-like RAW264.7 cells. The electrophoretic mobility shift assay revealed that 15d-PGJ2 enhanced the DNA binding of Nrf2. In addition, 15d-PGJ2 upregulated the expression of CD36, thereby stimulating efferocytosis. siRNA knockdown of Nrf2 abolished 15d-PGJ2-induced CD36 expression, resulting in reduced efferocytosis. embryonic fibroblasts from Nrf2-null mice failed to up-regulate CD36 expression upon 15d-PGJ2 treatment. Moreover, unlike 15d-PGJ2, its non-electrophilic analog 9,10-ihidro-15d-PGJ2 could not induce expression of Nrf2 and CD36, suggesting that the α,β-unsaturated carbonyl group located in the cyclopenenone ring of 15d-PGJ2 is essential for Nrf2-induced CD36 expression. Taken together, these results suggest that 15d-PGJ2 might expedite resolution of inflammation by activating efferocytosis which appears to be mediated through Nrf2-induced CD36 expression in macrophages. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 2572. doi:1538-7445.AM2012-2572