Proapoptotic activity of indoleamine 2,3-dioxygenase expressed in renal tubular epithelial cells.
Exposure of renal tubular epithelial cells (TEC) to IFN-gamma/TNF-alpha 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-gamma/TNF-alpha exposure. Increased IDO activity promoted TEC apoptosis, whereas inhibition of IDO by its specific inhibitor 1-methyl-d-tryptophan attenuated IFN-gamma/TNF-alpha-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.
Mohib
Kanishka
K
Department of Medicine and Microbiology, The University of Western Ontario, London, Ontario, Canada.
Guan
Qiunong
Q
Diao
Hong
H
Du
Caigan
C
Jevnikar
Anthony M
AM
D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D002478:Cells, Cultured; D004847:Epithelial Cells / Q000378:metabolism*; D053222:Fas Ligand Protein / Q000378:metabolism; D015971:Gene Expression Regulation, Enzymologic; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase / Q000235:genetics* / Q000378:metabolism*; D007371:Interferon-gamma / Q000378:metabolism; D007684:Kidney Tubules / Q000166:cytology*; D051379:Mice; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D015854:Up-Regulation; D019014:fas Receptor / Q000378:metabolism
D053222:Fas Ligand Protein; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase; D014409:Tumor Necrosis Factor-alpha; D019014:fas Receptor; D007371:Interferon-gamma