Abstract
Systemic inflammation has emerged as a key pathophysiological process that induces multi-organ injury and causes many diseases such as sepsis. Unfortunately, specific clinical treatment of controlling systemic inflammation is still lacking. Physiological metabolites and dietary metabolites are thought to play an important role in modulating inflammation and inflammatory diseases. We postulated that physiological and dietary metabolites might modulate inflammatory responses and protect against systemic inflammation. Diacylglycerols (or "diglycerides", DAGs) are natural components of vegetable oils and are extensively used in food oil as an emulsifier. They exist in three stereochemical forms, sn-1,2- and sn-2,3-diacylglycerols and sn-1,3-diacylglycerols. Despite substantial evidence supports the role of exogenous DAG in modulating chronic inflammation and chronic diseases, the potential mechanisms of it in metabolic inflammation modulation remains to be investigated. We find that sn-1,2-DAGs pretreatment suppresses LPS/TLR4-induced cyclooxygenase-2 (COX-2) expression and cytokines production in macrophages, but has no significant effect on other TLRs. Furthermore, sn-1,2-DAGs treatment improves the survival rate in LPS-induced lethal endotoxemic mice by suppressing proinflammatory cytokines and chemokines production. sn-1,2-diacylglycerols alleviate systemic inflammation by inhibiting LPS-induced p38 MAPK- and PI3K/AKT- mediated NF-κB activation in macrophages. Collectively, exogenous sn-1,2-diacylglycerol protects mice against LPS-induced lethal endotoxemia by suppressing TLR4-driven inflammatory responses. As dietary metabolites, endogenous physiological metabolite may have the ability to control systemic inflammation. Endothelium is critical in maintaining inflammatory homeostasis, controlling systemic inflammation, and progression of inflammatory diseases. We postulated that endothelium produces and releases endogenous soluble factors to modulate inflammatory responses and protect against systemic inflammation. The results indicate endothelial cells conditioned medium suppressed LPS-induced proinflammatory cytokines and COX-2 expression in macrophages. Using metabolic approach, we identified that the potential effective molecule is 5-methoxytryptophan (5-MTP). Furthermore, endothelial cells-derived 5-MTP suppressed LPS-induced inflammatory response in macrophages and endotoxemic lung tissues. Notably, LPS depressed 5-MTP production in endothelial cells and reduced serum 5-MTP level in the endotoxemic mice and patient with sepsis. Intraperitoneal injection of 5-MTP increased the serum level of 5-MTP and rescued mice from LPS- and CLP-mediated lethal systemic inflammation. These results suggest that endothelial cells produce 5-MTP to control the homeostasis of the inflammatory response. In summary, this study demonstrated that exogenous sn-1,2-diacylglycerol and endothelium-derived 5-MTP are capable of defending against excessive systemic inflammatory responses and may be useful as a dietary health supplements for prevention or therapy of systemic inflammatory diseases.