title: Interferon-γ induces a tryptophan-selective amino acid transporter in human colonic epithelial cells and mouse dendritic cells.
abstract: IDO1, which encodes the immunosuppressive and tryptophan-catabolizing enzyme indoleamine 2,3-dioxygenase-1 (IDO1), is a target for interferon-γ (IFN-γ). IDO1-mediated tryptophan catabolism in dendritic cells and macrophages arrests T cell proliferation, thereby providing a molecular basis for the immunosuppressive function of IDO1. Whether the entry of tryptophan into IDO1-expressing cells is also regulated by IFN-γ is not known. Here we used a human colonic epithelial cell line (CCD841) and a mouse dendritic cell line (DC2.4) to test the hypothesis that IFN-γ, which induces IDO1, also induces a tryptophan transporter to promote substrate availability to IDO1. Upon treatment with IFN-γ, there was a marked increase in IDO1 mRNA and a concomitant increase in tryptophan uptake in both cell lines. The induced uptake system was selective for tryptophan and saturable with a Michaelis constant of 36±3 μM in CCD841 cells and 0.5±0.1 μM in DC2.4 cells. The induction by IFN-γ and the tryptophan-selectivity of the induced transport system were demonstrable even in the presence of physiologic concentrations of all other amino acids. Since kynurenine, the catabolic end product of IDO1, is a signaling molecule as an agonist for the aryl hydrocarbon receptor (AhR), we examined if AhR signaling induces the tryptophan-selective transporter. Treatment of the cells with kynurenine and other AhR agonists increased tryptophan uptake. The present studies demonstrate that IFN-γ coordinately induces IDO1 and a tryptophan-selective transporter to maximize tryptophan depletion in IDO1-expressing cells and that the process involves a positive feedback mechanism via kynurenine-AhR signaling.
authors.affiliation: Department of Cell Biology and Biochemistry, Texas Tech University Health Sciences Center, Lubbock, TX 79430 USA. Electronic address: yangzom.d.bhutia@ttuhsc.edu.
authors.forename: Yangzom D
authors.initials: YD
authors.lastname: Bhutia
authors.affiliation: Department of Cell Biology and Biochemistry, Texas Tech University Health Sciences Center, Lubbock, TX 79430 USA.
authors.forename: Ellappan
authors.initials: E
authors.lastname: Babu
authors.affiliation: Department of Cell Biology and Biochemistry, Texas Tech University Health Sciences Center, Lubbock, TX 79430 USA.
authors.forename: Vadivel
authors.initials: V
authors.lastname: Ganapathy
mesh_terms: D026905:Amino Acid Transport Systems / Q000819:agonists / Q000235:genetics* / Q000378:metabolism; D000818:Animals; D001692:Biological Transport; D002460:Cell Line; D003106:Colon / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D003713:Dendritic Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D004847:Epithelial Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D025461:Feedback, Physiological; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D006801:Humans; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase / Q000235:genetics* / Q000378:metabolism; D007371:Interferon-gamma / Q000378:metabolism / Q000494:pharmacology*; D007700:Kinetics; D007737:Kynurenine / Q000378:metabolism; D051379:Mice; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D018336:Receptors, Aryl Hydrocarbon / Q000235:genetics* / Q000378:metabolism; D015398:Signal Transduction; D014364:Tryptophan / Q000378:metabolism*
chemical_list: D026905:Amino Acid Transport Systems; C576710:IDO1 protein, human; C583637:IDO1 protein, mouse; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase; D012333:RNA, Messenger; D018336:Receptors, Aryl Hydrocarbon; D007737:Kynurenine; D007371:Interferon-gamma; D014364:Tryptophan
keywords: Aryl hydrocarbon receptor; Colonic epithelial cell; Dendritic cell; Indoleamine 2,3-dioxygenase; Interferon-γ; Tryptophan-selective amino acid transport