title: sn-1,2-diacylglycerols protect against lethal endotoxemia by controlling systemic inflammation.
abstract: Systemic inflammation has emerged as a key pathophysiological process that induces multiple organ injuries and causes serious human diseases. Despite substantial evidence supporting the role of diacylglycerols (DAG) in modulating chronic inflammation and chronic diseases, the potential mechanisms of its involvement in TLRs-mediated inflammation are still unclear. Here, we show that sn-1,2-diacylglycerols modulate LPS/TLR4-mediated inflammation in vitro and in vivo. ELISA and western blotting experiments indicated that sn-1,2-diacylglycerols suppress LPS-induced responses, including IL-6 and TNF-α production, and COX-2 expression in mouse RAW264.7 macrophages and human endothelial cells, in a dose-dependent manner. Using LPS-induced murine model of systemic inflammation, we show that sn-1,2-diacylglycerols block the cytokine storm, the expression of inflammatory mediators, and LPS-induced septic lung damage and mortality. sn-1,2-diacylglycerols reduce systemic inflammation by inhibiting LPS-induced p38 MAPK- and PI3K/AKT-mediated NF-κB activation in macrophages. These results suggest that exogenous DAG probably acts by blocking p38 MAPK or PI3K/AKT signal transduction, thereby down-regulating NF-κB activation and NF-κB-mediated transcription of genes encoding cytokines and pro-inflammatory oxidative enzymes. Our findings demonstrate that exogenous sn-1,2-diacylglycerol protects mice from LPS-induced lethal endotoxemia by suppressing TLR4-driven inflammatory responses, suggesting that 1,2-diacylglycerols may be used as dietary health supplements for the prevention or therapy of systemic inflammatory diseases.
authors.affiliation: Institute of Cellular and System Medicine, National Health Research Institutes, Zhunan, Taiwan; Institute of Molecular Medicine, National Tsing Hua University, Hsinchu, Taiwan.
authors.forename: Yi-Fu
authors.initials: YF
authors.lastname: Wang
authors.affiliation: Institute of Molecular Medicine, National Tsing Hua University, Hsinchu, Taiwan; Graduate Institutes of Life Sciences and Biochemistry, National Defense Medical Center, Taipei, Taiwan.
authors.forename: Guan-Lin
authors.initials: GL
authors.lastname: Lee
authors.affiliation: Institute of Molecular Medicine, National Tsing Hua University, Hsinchu, Taiwan.
authors.forename: Yu-Hua
authors.initials: YH
authors.lastname: Huang
authors.affiliation: Institute of Cellular and System Medicine, National Health Research Institutes, Zhunan, Taiwan; Graduate Institutes of Life Sciences and Biochemistry, National Defense Medical Center, Taipei, Taiwan; Metabolomic Research Center, China Medical University Hospital, Taichung, Taiwan; Graduate Institute of Basic Medical Science, China Medical University, Taichung, Taiwan. Electronic address: kuocc@nhri.org.tw.
authors.forename: Cheng-Chin
authors.initials: CC
authors.lastname: Kuo
mesh_terms: D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology*; D015415:Biomarkers; D002460:Cell Line; D051546:Cyclooxygenase 2 / Q000378:metabolism; D016207:Cytokines / Q000378:metabolism; D004075:Diglycerides / Q000494:pharmacology*; D004195:Disease Models, Animal; D042783:Endothelial Cells / Q000378:metabolism; D019446:Endotoxemia / Q000188:drug therapy / Q000276:immunology* / Q000378:metabolism* / Q000401:mortality; D006801:Humans; D008070:Lipopolysaccharides / Q000276:immunology; D008264:Macrophages / Q000276:immunology / Q000378:metabolism; D051379:Mice; D020011:Protective Agents / Q000494:pharmacology*; D015398:Signal Transduction / Q000187:drug effects
chemical_list: C011439:1,2-diacylglycerol; D000893:Anti-Inflammatory Agents; D015415:Biomarkers; D016207:Cytokines; D004075:Diglycerides; D008070:Lipopolysaccharides; D020011:Protective Agents; D051546:Cyclooxygenase 2
keywords: Diacylglycerol; Systemic inflammation; TLR4