We identified in the conditioned medium of human fibroblasts a tryptophan metabolite, 5-methoxytryptophan (5-MTP) which controls cyclooxgenase-2 expression and inhibits NF-κB binding and p300 activity. We postulated that as with fibroblasts, human endothelial cells produce 5-MTP which plays an important role in controlling systemic inflammatory responses. Human endothelial cells produced and released 5-MTP into the conditioned medium. Lipopolysaccharide (LPS) suppressed 5-MTP production in endothelial cells and induced 5-MTP deficiency in the murine sepsis model. Intraperitoneal infusion of 5-MTP restored serum 5-MTP accompanied by inhibition of systemic pro-inflammatory cytokines, chemokines, and pro-inflammatory mediators. 5-MTP administration rescued organ failure and prevented mortality. The beneficial effect of 5-MTP was correlated with inhibition of cytokine production and COX-2 expression in macrophages. 5-MTP inhibited LPS-induced p38 MAPK, p300 HAT and NF-κB activation in macrophages and endotoxemic lung tissues in vivo. Importantly, a considerable amount of 5-MTP was detected in 30 healthy subjects (1.05 ± 0.39 μM) which was significantly reduced in 50 sepsis patients (0.37 ± 0.15 μM, p<0.0001). 5-MTP is a novel circulating anti-inflammatory molecule which protects against excessive systemic inflammatory responses. It ameliorates LPS-induced sepsis and is a valuable lead compound for developing new drugs to treat sepsis and systemic inflammatory disorders.
Date:
2015-05
Relation:
Journal of Immunology. 2015 May;194(1 Suppl.):Meeting Abstract 132.1.
