Exposure of renal tubular epithelial cells (TEC) to IFN-γ/TNF-α leads to Fas/FasL-mediated self-injury, which contributes to allograft rejection. Indoleamine 2,3-dioxygenase (IDO) converts tryptophan to N-formyl-kynurenine and contributes to immune privilege in tissues by increasing Fas-mediated T cell apoptosis. However, renal expression of IDO and its role in promoting Fas-mediated TEC death have not been examined. IDO expression was analyzed by RT-PCR and Western blot. Apoptosis was measured by fluorescence-activated cell sorting analysis and terminal deoxytransferase-mediated dUTP nick end labeling. We demonstrated that functional IDO is expressed in TEC and is increased by IFN-γ/TNF-α exposure. Increased IDO activity promoted TEC apoptosis, whereas inhibition of IDO by its specific inhibitor 1-methyl-d-tryptophan attenuated IFN-γ/TNF-α-mediated TEC apoptosis and augmented TEC survival. Transgenic expression of IDO resulted in increased TEC apoptosis in the absence of proinflammatory cytokine exposure, supporting a central role for IDO in TEC injury. Inhibition of IDO-mediated TEC death by a caspase-8-specific inhibitor (Z-IETD-FMK), as well as the absence of an IDO effect in Fas-deficient and FasL-deficient TEC, supports a Fas/FasL-dependent, caspase-8-mediated mechanism for IDO-enhanced TEC death. These data suggest that renal IDO expression may be deleterious during renal inflammation, because it enhances TEC self-injury through Fas/FasL interactions. Thus attenuation of IDO may represent a novel strategy to promote kidney function following ischemia and renal allograft rejection.
HIV-1 viral protein r induces ERK and caspase-8-dependent apoptosis in renal tubular epithelial cells