title: Bimodal effect of nitric oxide in the enzymatic activity of indoleamine 2,3-dioxygenase in human monocytic cells.
abstract: Indoleamine 2,3-dioxygenase (IDO) is an enzyme that depletes l-tryptophan, which provokes a decreased T cell response. This enzyme is expressed in human placenta, and can be also induced in many cell types such as monocytes, where endothelial (eNOS) and inducible (iNOS) nitric oxide synthases are also expressed. Previous studies have shown that nitric oxide (NO) inhibits IDO activity, which could cause a suppression of the biological function of IDO when both enzymes are coexpressed. As NO can exert different effects depending on several factors such as its concentration, we studied the effect of low concentrations of NO in the IDO activity in the U-937 and THP-1 monocytic cell lines. Results demonstrated that NO caused a bimodal effect in IDO function in IFN-gamma-stimulated monocytic cells: while high micromolar concentrations of the NO donors SIN-1 and DETA-NO decreased IDO activity, low micromolar concentrations of these NO donors increased IDO activity. Related to this, the NOS inhibitors L-NMMA and aminoguanidine, and the calmodulin antagonist W7 also decreased IDO activity. The effect of NO in IDO activity was not through cGMP production. Immunoprecipitation analysis showed a nitration of the IDO protein in unstimulated and stimulated U-937 and THP-1 cells. However, in monocyte-derived macrophages, with a higher NO production, aminoguanidine increased IDO activity, but the NOS substrate arginine decreased IDO activity. Considering the role of IDO in suppression, these results suggest a function in tolerance of the NOS enzymes depending on the NO production.
authors.affiliation: Department of Clinical Biochemistry, Clínica Universitaria de Navarra, Av. Pío XII 36, 31008 Pamplona, Spain.
authors.forename: Ana S
authors.initials: AS
authors.lastname: López
authors.forename: Estíbaliz
authors.initials: E
authors.lastname: Alegre
authors.forename: Angel
authors.initials: A
authors.lastname: Díaz
authors.forename: Carmen
authors.initials: C
authors.lastname: Mugueta
authors.forename: Alvaro
authors.initials: A
authors.lastname: González
mesh_terms: D004305:Dose-Response Relationship, Drug; D004789:Enzyme Activation / Q000187:drug effects / Q000276:immunology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006801:Humans; D007108:Immune Tolerance / Q000187:drug effects / Q000276:immunology; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D007371:Interferon-gamma / Q000276:immunology / Q000494:pharmacology; D008981:Molsidomine / Q000031:analogs & derivatives / Q000494:pharmacology; D009000:Monocytes / Q000201:enzymology* / Q000276:immunology; D009569:Nitric Oxide / Q000276:immunology / Q000378:metabolism*; D020030:Nitric Oxide Donors / Q000494:pharmacology; D052247:Nitric Oxide Synthase Type II / Q000037:antagonists & inhibitors / Q000276:immunology / Q000378:metabolism; D052250:Nitric Oxide Synthase Type III / Q000037:antagonists & inhibitors / Q000276:immunology / Q000378:metabolism; D013449:Sulfonamides / Q000494:pharmacology; D014226:Triazenes / Q000494:pharmacology; D020298:U937 Cells; D019323:omega-N-Methylarginine / Q000494:pharmacology
chemical_list: C105351:1-hydroxy-2-oxo-3,3-bis(2-aminoethyl)-1-triazene; D004791:Enzyme Inhibitors; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase; D020030:Nitric Oxide Donors; D013449:Sulfonamides; D014226:Triazenes; D019323:omega-N-Methylarginine; D009569:Nitric Oxide; C002385:linsidomine; C017967:W 7; D007371:Interferon-gamma; D008981:Molsidomine; C496314:NOS3 protein, human; D052247:Nitric Oxide Synthase Type II; D052250:Nitric Oxide Synthase Type III