Endothelium-Derived 5-Methoxytryptophan Is a Circulating Anti-Inflammatory Molecule That Blocks Systemic Inflammation

Abstract

Rationale: Systemic inflammation has emerged as a key pathophysiological process that induces multiorgan injury and causes serious human diseases. Endothelium is critical in maintaining cellular and 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. Objective: To identify endothelial cell–released soluble factors that protect against endothelial barrier dysfunction and systemic inflammation. Methods and Results: We found that conditioned medium of endothelial cells inhibited cyclooxgenase-2 and interleukin-6 expression in macrophages stimulated with lipopolysaccharide. Analysis of conditioned medium extracts by liquid chromatography–mass spectrometry showed the presence of 5-methoxytryptophan (5-MTP), but not other related tryptophan metabolites. Furthermore, endothelial cell–derived 5-MTP suppressed lipopolysaccharide-induced inflammatory responses and signaling in macrophages and endotoxemic lung tissues. Lipopolysaccharide suppressed 5-MTP level in endothelial cell-conditioned medium and reduced serum 5-MTP level in the murine sepsis model. Intraperitoneal injection of 5-MTP restored serum 5-MTP accompanied by the inhibition of lipopolysaccharide-induced endothelial leakage and suppression of lipopolysaccharide- or cecal ligation and puncture–mediated proinflammatory mediators overexpression. 5-MTP administration rescued lungs from lipopolysaccharide-induced damages and prevented sepsis-related mortality. Importantly, compared with healthy subjects, serum 5-MTP level in septic patients was decreased by 65%, indicating an important clinical relevance. Conclusions: We conclude that 5-MTP belongs to a novel class of endothelium-derived protective molecules that defend against endothelial barrier dysfunction and excessive systemic inflammatory responses.

New Member of Endothelial Arsenal Against Inflammation

“…In terms of future directions, this report 20 opens the door for investigations of the specific stimuli leading to production of 5-MTP, the cellular mechanisms of action of 5-MTP, and the pathways through which it is exported. Because the authors determined the location of 5-MTP in the cytoplasm and because eNOS translocation from the cell membrane to the cytosol is a requirement for the development of hyperpermeability 21–24 , it is tempting to speculate that 5-MTP may reduce transport of macromolecules across microvascular walls by returning eNOS from the cytoplasm to the cell membrane or by inhibiting the synthesis of eNOS-derived NO in the cytoplasm.…”

“…Wang et al 20 add a new molecule of endothelial origin as an anti-inflammatory agent in their article "Endothelium-derived 5-methoxytryptophan is a circulating anti-inflammatory molecule that blocks systemic inflammation" in this issue of Circulation Research . The authors extracted and identified 5-methoxytryptophan (5-MTP) from endothelial cell-conditioned medium (EC-CM).…”

“…The authors extracted and identified 5-methoxytryptophan (5-MTP) from endothelial cell-conditioned medium (EC-CM). While it is known that other cells make 5-MTP, one of the merits of the work by Wang and colleagues 20 is the demonstration that endothelial cells produce 5-MTP. They conducted a series of logically designed experiments to ascertain the role of 5-MTP in inflammation using accepted in vitro and in vivo models of endotoxemia (LPS, in vitro - HUVEC) and sepsis (cecal ligation and puncture, in vivo - in mice) as well as in a translational manner in patients.…”

“…Wang et al 20 showed the translational potential of the their research through results revealing a decrease in 5-MTP concentration in the blood of septic patients, which suggest that an increase in 5-MTP may yield benefits to improve health. Through comparison of 5-MTP concentrations in the blood of different groups of patients, the authors concluded that 5-MTP is a marker of systemic inflammation – but it does not report the stage of progression of sepsis.…”

“…The balance of our knowledge shows predominance of pro-inflammatory agents, and relative paucity of endothelial antiinflammatory molecules. The report by Wang et al 20 rekindles the interest in identifying and exploring regulatory factors produced by endothelial and/or vascular cells.…”