l-Kynurenine-induced apoptosis in human NK cells is mediated by reactive oxygen species

Recent studies have shown that indoleamine 2,3-dioxygenase (IDO) plays a pivotal role in the modulation of immune response against tumor and virus infection. Here we demonstrate the pro-apoptotic effect of l-kynurenine, a tryptophan catabolite of IDO, on human NK cell line, NK92 MI. Treatment with l-kynurenine dose-dependently induced growth inhibition and apoptosis in NK92 MI cells. Treatment with the antioxidant NAC completely protected cells from l-kynurenine-induced apoptosis. Moreover, we found that treatment with Z-VAD-fmk and ZB4 slightly inhibited l-kynurenine-induced apoptosis, suggesting that l-kynurenine-induced apoptosis in NK cells occurs primarily through an ROS mediated pathway. We observed that the presence of NAC blocks cytochrome c release and activation of caspase-3 during l-kynurenine-induced apoptosis. Overall, we conclude that l-kynurenine resulting from IDO can cause cell death via ROS pathway in NK cells. Our findings provide a new insight into the interaction between NK cells and IDO positive cancer cells in regulating immune responses.