L-Kynurenine

L-Kynurenine is a metabolite of L-tryptophan and an aryl hydrocarbon receptor (AhR) agonist. L-Kynurenine can also cause NK cell death through the reactive oxygen species (ROS) pathway^[1][2].

L-Kynurenine triggers competition between aryl hydrocarbon receptor and hypoxia-inducible factor 1 alpha (HIF-1α) for ARNT (Aryl Hydrocarbon Receptor Nuclear Translocator) in MCF-7 cells under hypoxic conditions ^[1]. L-Kynurenine (0-1mM; 48h) specifically affects the expression of NKp46, NKG2D, and CD69 in the phenotype of NK cells cultured in IL-2, without altering the surface density of other triggering or coreceptors, including CD16, 2B4, NTB-A, DNAM-1, and CD59, or the surface density of inhibitory receptors^[2]. After adding L-Kynurenine (10-40µM) to the supernatant of HCEC cells, cell apoptosis increased slightly and had a certain dose-dependent toxicity ^[3]. Treatment with L-Kynurenine (0–800μM; 72h) dose-dependently induced growth inhibition and apoptosis in NK92 MI cells^[4].

L-Kynurenine (30mg/kg) inhibited ischemia-induced hyperlocomotion in the mouse MCAO model and reduced ischemia-induced deterioration of spontaneous alternation (a measure of spatial memory) without changing rectal temperature^[5]. In the rat L5/L6 spinal nerve ligation model, L-Kynurenine (50-200mg/kg; ip) did not affect allodynia in neuropathic rats, while the combination of L-Kynurenine and the organic anion transport inhibitor probenecid (100mg/kg; ip) reversed allodynia^[6].

References:
[1]. Cuartero M I, Ballesteros I, de la Parra J, et al. L-kynurenine/aryl hydrocarbon receptor pathway mediates brain damage after experimental stroke[J]. Circulation, 2014, 130(23): 2040-2051.
[2]. Schlichtner S, Yasinska I M, Klenova E, et al. L-Kynurenine participates in cancer immune evasion by downregulating hypoxic signaling in T lymphocytes[J]. OncoImmunology, 2023, 12(1): 2244330.
[3]. Chiesa M D, Carlomagno S, Frumento G, et al. The tryptophan catabolite L-kynurenine inhibits the surface expression of NKp46-and NKG2D-activating receptors and regulates NK-cell function[J]. Blood, 2006, 108(13): 4118-4125.
[4]. Serbecic N, Lahdou I, Scheuerle A, et al. Function of the tryptophan metabolite, L-kynurenine, in human corneal endothelial cells[J]. Molecular vision, 2009, 15: 1312.
[5]. Gigler G, Szénási G, Simó A, et al. Neuroprotective effect of L-kynurenine sulfate administered before focal cerebral ischemia in mice and global cerebral ischemia in gerbils[J]. European journal of pharmacology, 2007, 564(1-3): 116-122.
[6]. Pineda‐Farias J B, Pérez‐Severiano F, González‐Esquivel D F, et al. The l‐kynurenine–probenecid combination reduces neuropathic pain in rats[J]. European journal of pain, 2013, 17(9): 1365-1373.

L-Kynurenine是L-色氨酸的代谢物，也是一种芳香烃受体 (aryl hydrocarbon receptor; AhR) 激动剂^[1][2]。

在缺氧条件下，L-Kynurenine会引发芳香烃受体和缺氧诱导因子1α（HIF-1α）竞争MCF-7细胞中的ARNT（Aryl Hydrocarbon Receptor Nuclear Translocator，芳基烃受体核转位子）^[1]。L-Kynurenine（0-1mM；48h）特异性影响在IL-2中培养的NK细胞表型中NKp46、NKG2D和CD69的表达，而不会改变其他触发或辅助受体的表面密度，包括CD16、2B4、NTB-A、DNAM-1和CD59，或抑制性受体的表面密度^[2]。HCEC细胞上清液中加入L-Kynurenine（10-40µM）后，细胞凋亡略有增加，并具有一定的剂量依赖性毒性^[3]。L-Kynurenine（0-800μM；72h)处理NK92 MI细胞，可剂量依赖性地诱导生长抑制和细胞凋亡^[4]。

L-Kynurenine（30mg/kg）在不改变直肠温度的条件下抑制了小鼠MCAO模型中缺血引起的运动亢进，并降低了缺血引起的自发交替恶化（一种空间记忆的衡量标准）^[5]。在大鼠L5/L6脊神经结扎模型中，L-Kynurenine（50-200mg/kg；ip）不影响神经病大鼠的异常性疼痛，而L-Kynurenine和有机阴离子转运抑制剂丙磺舒（100mg/kg；ip）联合使用可逆转异常性疼痛^[6]。