HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Full Text Full Text (PDF) All Versions of this Article: 293/3/F801    most recent 00044.2007v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in ISI Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via ISI Web of Science (1) Citing Articles via Google Scholar Google Scholar Articles by Mohib, K. Articles by Jevnikar, A. M. Search for Related Content PubMed PubMed Citation Articles by Mohib, K. Articles by Jevnikar, A. M.

Proapoptotic activity of indoleamine 2,3-dioxygenase expressed in renal tubular epithelial cells

¹Departments of Medicine and Microbiology and Immunology, The University of Western Ontario, London, Ontario; ²The Robarts Research Institute, London, Ontario; ³The Lawson Health Research Institute, London, Ontario; and ⁴The Multi-Organ Transplant Program, London Health Sciences Center, London, Ontario, Canada

Submitted 27 January 2007 ; accepted in final form 28 June 2007

Exposure of renal tubular epithelial cells (TEC) to IFN-/TNF- 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-/TNF- exposure. Increased IDO activity promoted TEC apoptosis, whereas inhibition of IDO by its specific inhibitor 1-methyl-D-tryptophan attenuated IFN-/TNF--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.

tubular epithelium; apoptosis

This article has been cited by other articles:

				K. Mohib, S. Wang, Q. Guan, A. L. Mellor, H. Sun, C. Du, and A. M. Jevnikar Indoleamine 2,3-dioxygenase expression promotes renal ischemia-reperfusion injury Am J Physiol Renal Physiol, July 1, 2008; 295(1): F226 - F234. [Abstract] [Full Text] [PDF]

				A. M. Jevnikar and R. B. Mannon Late Kidney Allograft Loss: What We Know about It, and What We Can Do about It Clin. J. Am. Soc. Nephrol., March 1, 2008; 3(Supplement_2): S56 - S67. [Abstract] [Full Text] [PDF]