Abstract 847: Resolvin D1 stimulates efferocytosis through p50/p50-mediated suppression of tumor necrosis factor-α

Abstract

Abstract Phagocytosis of apoptotic neutrophils by macrophages, called efferocytosis, is critical to resolution of inflammation as this process prevents the exposure of surrounding tissues at the inflammatory site to the toxic contents of lytic cells. Docosahexaenoic acid-derived resolvin D1 (RvD1), endogenously generated during resolution of inflammation, is known to stimulate efferocytosis, but little is known about the mechanism of its action. In the present study, we found that lipopolysaccharide (LPS; 200 μg/ml) suppressed efferocytosis by murine macrophage-like RAW264.7 cells, and RvD1 (50 nM) restored the phagocytic ability of these cells by down-regulating TNF-α expression. The inhibitory effect of RvD1 on LPS-induced TNF-α expression was associated with enhanced nuclear localization of p50/p50 homodimer and concomitant reduction in the nuclear levels of p65/p50 heterodimer. RvD1 triggered extracellular signal-regulated kinase (ERK)- and Akt-mediated nuclear factor κB1 (NF-κB1) p105 degradation and subsequently translocation of p50/p50 homodimer to nucleus in RAW264.7 cells. In contrast, LPS-induced nuclear translocation and DNA binding of p65/p50 heterodimer were attenuated by RvD1 treatment through inhibition of IκBα degradation. siRNA knockdown of NF-κB p50 abolished RvD1-mediated suppression of TNF-α expression and resulted in impaired efferocytosis, suggesting that the replacement of p65/p50 with p50/p50 homodimer is an essential event for RvD1-mediated stimulation of efferocytosis. In a murine peritonitis model, intraperitoneal administration of RvD1 (300 ng) abrogated zymosan A (30 mg/kg)-induced TNF-α production, thereby reactivating efferocytosis. In addition, RvD1 significantly reduced polymorphonuclear leukocyte infiltration while it increased monocyte infiltration. Taken together, these findings indicate that RvD1 expedites resolution of inflammation via p50/p50-mediated repression of TNF-α production. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 847. doi:10.1158/1538-7445.AM2011-847