carbon monoxide induced pparγ sumoylation and ucp2 block inflammatory gene expression in macrophages一氧化碳诱导pparγsumoylation和ucp2阻止炎症巨噬细胞基因表达.pdfVIP

Carbon Monoxide Induced PPARc SUMOylation and UCP2 Block Inflammatory Gene Expression in Macrophages 1. 2. 1 1 1 Arvand Haschemi , Beek Yoke Chin , Markus Jeitler , Harald Esterbauer , Oswald Wagner , Martin Bilban1.*, Leo E Otterbein2. 1 Department of Laboratory Medicine, Medical University of Vienna, Vienna, Austria, 2 Department of Surgery, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts, United States of America Abstract Carbon monoxide (CO) dampens pro-inflammatory responses in a peroxisome proliferator-activated receptor-c (PPARc) and p38 mitogen-activated protein kinase (MAPK) dependent manner. Previously, we demonstrated that CO inhibits lipopolysaccharide (LPS)-induced expression of the proinflammatory early growth response-1 (Egr-1) transcription factor in macrophages via activation of PPARc. Here, we further characterize the molecular mechanisms by which CO modulates the activity of PPARc and Egr-1 repression. We demonstrate that CO enhances SUMOylation of PPARc which we find was attributed to mitochondrial ROS generation. Ectopic expression of a SUMOylation-defective PPARc-K365R mutant partially abolished CO-mediated suppression of LPS-induced Egr-1 promoter activity. Expression of a PPARc-K77R mutant did not impair the effect of CO. In addition to PPARc SUMOylation, CO-activated p38 MAPK was responsible for Egr-1 repression. Blocking both CO-induced PPARc SUMOylation and p38 activation, completely reversed the effects of CO on inflammatory gene expression. In primary macrophages isolated form C57/BL6 male mice, we identify mitochondrial ROS formation by CO as the upstream trigger for the observed effects on Egr-1 in part