National Health Research Institutes, Taiwan
Title: Endothelium-derived 5-Methoxytryptophan acts as a therapeutic biomarker for systemic inflammation
Biography: Cheng Chin Kuo
Systemic inflammation has emerged as a key pathophysiological process which induces multi-organ injury and causes serious human diseases. Endothelium plays a critical role in maintaining cellular and inflammatory homeostasis, 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. We found that conditioned medium (CM) of endothelial cell (EC) inhibited cyclooxgenase-2 (COX-2) and interleukin-6 expression in macrophages stimulated with lipopolysaccharide (LPS). Analysis of CM extracts by liquid chromatography–mass spectrometry (LC-MS) showed the presence of 5-methoxytryptophan (5-MTP) but no other related tryptophan metabolites. Furthermore, endothelial cells-derived 5-MTP suppressed LPS-induced inflammatory responses and signaling in macrophages and endotoxemic lung tissues. LPS suppressed 5-MTP level in EC-CM and reduced serum 5-MTP level in the murine sepsis model. Intraperitoneal injection of 5-MTP restored serum 5-MTP accompanied by inhibition of LPS-induced endothelial leakage and suppression of LPS- or cecal ligation and puncture (CLP)-mediated pro-inflammatory mediators overexpression. 5-MTP administration rescued lungs from LPS-induced damages and prevented sepsis-related mortality. Importantly, a considerable amount of 5-MTP was detected in healthy subjects (1.05±0.39 M) while 5-MTP level in septic patients (0.37±0.15 M, p<0.0001) was significantly reduced in septic patients. We conclude that 5-MTP belongs to a novel class of endothelium-derived protective molecules which defend against endothelial barrier dysfunction and excessive systemic inflammatory responses. Being an endogenously produced compound, 5-MTP has the advantage of having less unexpected adverse effects. Thus, 5-MTP will be a valuable lead compound for new inflammatory drug development. Another potential clinical application of 5-MTP is its use as a biomarker of sepsis and other systemic inflammatory disorders. Hence, it may be useful as a “Therapeutic” biomarker for selecting sepsis patients for 5-MTP therapy.