Effect Of L-kynurenine Research Articles

On the Antioxidant Properties of L-Kynurenine: An Efficient ROS Scavenger and Enhancer of Rat Brain Antioxidant Defense.

L-kynurenine (L-KYN) is an endogenous metabolite, that has been used as a neuroprotective strategy in experimental models. The protective effects of L-KYN have been attributed mainly to kynurenic acid (KYNA). However, considering that L-KYN is prone to oxidation, this redox property may play a substantial role in its protective effects. The aim of this work was to characterize the potential impact of the redox properties of L-KYN, in both synthetic and biological systems. First, we determined whether L-KYN scavenges reactive oxygen species (ROS) and prevents DNA and protein oxidative degradation in synthetic systems. The effect of L-KYN and KYNA (0.1–100 µM) on redox markers (ROS production, lipoperoxidation and cellular function) was compared in rat brain homogenates when exposed to FeSO4 (10 µM). Then, the effect of L-KYN administration (75 mg/kg/day for 5 days) on the GSH content and the enzymatic activity of glutathione reductase (GR) and glutathione peroxidase (GPx) was determined in rat brain tissue. Finally, brain homogenates from rats pretreated with L-KYN were exposed to pro-oxidants and oxidative markers were evaluated. The results show that L-KYN is an efficient scavenger of ●OH and ONOO−, but not O2●– or H2O2 and that it prevents DNA and protein oxidative degradation in synthetic systems. L-KYN diminishes the oxidative effect induced by FeSO4 on brain homogenates at lower concentrations (1 µM) when compared to KYNA (100 µM). Furthermore, the sub-chronic administration of L-KYN increased the GSH content and the activity of both GR and GPx, and also prevented the oxidative damage induced by the ex vivo exposure to pro-oxidants. Altogether, these findings strongly suggest that L-KYN can be considered as a potential endogenous antioxidant.

Differential Distribution of Tryptophan-Metabolites in Fetal and Maternal Circulations During Normotensive and Preeclamptic Pregnancies.

Preeclampsia (PE) is a hypertensive pregnancy, which is a leading cause of maternal and fetal morbidity and mortality during pregnancy. L-Tryptophan (Trp) is an essential amino acid, which can be metabolized into various biologically active metabolites. However, the levels of many circulating Trp-metabolites in human normotensive pregnancies (NT) and PE are undetermined. This study quantified the levels of Trp-metabolites in maternal and umbilical vein sera from women with NT and PE. Paired maternal and umbilical blood samples were collected from singleton pregnant patients. Twenty-five Trp-metabolites were measured in serum samples using liquid chromatography with tandem mass spectrometry. The effects of L-kynurenine (Kyn) and indole-3-lactic acid (ILA), on function of human umbilical vein endothelial cells (HUVECs), were also determined. Twenty Trp-metabolites were detected. The levels of 9 Trp-metabolites including Kyn and ILA were higher (P < 0.05) in umbilical vein than maternal serum, whereas 2 (5-hydroxy-L-tryptophan and serotonin) were lower (P < 0.05) in umbilical vein compared to maternal serum. PE significantly (P < 0.05) elevated ILA levels in maternal and umbilical vein sera. Kyn dose-dependently decreased (P < 0.05) cell viability. Kyn and ILA dose- and time-dependently (P < 0.05) increased monolayer integrity in HUVECs. These data suggest that these Trp-metabolites are important in regulating endothelial function during pregnancy, and the elevated ILA in PE may antagonize increased endothelial permeability occurring in PE.

IDO metabolite produced by EBV-transformed B cells inhibits surface expression of NKG2D in NK cells via the c-Jun N-terminal kinase (JNK) pathway

Natural Killer cells are known to play a major role in the innate immune response against viral infections and tumor cells. Several viruses, such as CMV, EBV and HIV-1, have acquired strategies to escape elimination by NK cells. In this study, we observed that EBV infection increased expression of IDO on B cells. To evaluate the function of IDO associated with EBV infection, we investigated whether EBV-induced IDO could modulate expression of NK cell-activation receptor, NKG2D. When NK cells were co-incubated with EBV transformed B cells, surface expression of NKG2D was significantly reduced in NK cells. Incubation with L-kynurenine, an IDO metabolite, down-modulated NKG2D expression in NK cells in a dose- and time-dependent manner. Incubation with the JNK inhibitor SP600125 also inhibited NKG2D expression in NK cells. In addition, we observed that the effect of L-kynurenine was blocked by JNK agonist, anisomycin, suggesting the involvement of the JNK pathway in the signal transduction of L-kynurenine-reduced NKG2D expression. Furthermore, IL-18 significantly reduced L-kynurenine-induced down-regulation of NKG2D expression in NK cells. Taken together, these data indicate that down-regulation of NKG2D by EBV-induced IDO metabolite provides a potential mechanism by which EBV escapes NKG2D-mediated attack by immune cells.

The tryptophan catabolite l-kynurenine inhibits the surface expression of NKp46- and NKG2D-activating receptors and regulates NK-cell function

AbstractTryptophan (Trp) catabolism mediated by indoleamine 2,3-dioxygenase (IDO) plays a central role in the regulation of T-cell–mediated immune responses. In this study, we also demonstrate that natural killer (NK)–cell function can be influenced by IDO. Indeed, l-kynurenine, a Trp-derived catabolite resulting from IDO activity, was found to prevent the cytokine-mediated up-regulation of the expression and function of specific triggering receptors responsible for the induction of NK-cell–mediated killing. The effect of l-kynurenine appears to be restricted to NKp46 and NKG2D, while it does not affect other surface receptors such as NKp30 or CD16. As a consequence, l-kynurenine–treated NK cells display impaired ability to kill target cells recognized via NKp46 and NKG2D. Instead, they maintain the ability to kill targets, such as dendritic cells (DCs), that are mainly recognized via the NKp30 receptor. The effect of l-kynurenine, which is effective at both the transcriptional and the protein level, can be reverted, since NK cells were found to recover their functional competence after washing.