Indoleamine-2,3-dioxygenase activity in experimental human endotoxemia

Six healthy male volunteers were given E. coli lipopolysaccharide (LPS; 4 ng/kg) as a 1-min intravenous infusion. They had levels of soluble E-Selectin and soluble vascular cell adhesion molecule-1 as well as IDO activity assessed as the kynurenine-to-tryptophan plasma ratio by liquid chromatography-tandem mass spectrometry at various time points during a 24 h time course. During endotoxemia, IDO activity significantly increased, reaching peak levels at 8 h after LPS infusion (44.0 ± 15.2 vs. 29.4 ± 6.8 at baseline, P<0.0001). IDO activity correlated inversely with the development of hypotension as shown by random effects linear regression models. Finally, IDO activity exhibited a kinetic profile similar to that of soluble endothelial-specific adhesion molecules.LPS is a triggering factor for the induction of IDO in men. Our findings strongly support the concept that the induction of IDO in the vascular endothelium contributes to hypotension in human sepsis.Loss of vascular tone is an important factor in the development of severe sepsis, septic shock and multiple organ failure. Recent work by Wang and colleagues provided experimental evidence that kynurenine, a metabolite of the amino acid L-tryptophan, is a mediator of vasodilation and subsequent hypotension during murine endotoxemia [1]. In different mouse models of sepsis and additional in vitro experiments, they found that kynurenine acts as a novel endothelium-derived relaxing factor on resistance vessels by stimulating the activity of soluble guanylyl cyclase and adenylyl cyclase in smooth muscle cells. In addition the authors could show that injecting mice with bacterial lipopolysaccharide (LPS) specifically induces the rate-limiting enzyme for kynurenine production, namely indoleamine 2,3-dioxygenase 1 (IDO), in vascular endothelial cells [1]. Consistent with these findings, pharmacological blockade or genetic deletion of IDO increases survival in murine endotoxemia [2]. However, animal studies are potential