title: Cyclooxygenase-2 (COX-2) inhibition constrains indoleamine 2,3-dioxygenase 1 (IDO1) activity in acute myeloid leukaemia cells.
abstract: Indoleamine 2,3-dioxygenase 1 (IDO1) metabolizes L-tryptophan to kynurenines (KYN), inducing T-cell suppression either directly or by altering antigen-presenting-cell function. Cyclooxygenase (COX)-2, the rate-limiting enzyme in the synthesis of prostaglandins, is over-expressed by several tumours. We aimed at determining whether COX-2 inhibitors down-regulate the IFN-g-induced expression of IDO1 in acute myeloid leukaemia (AML) cells. IFN-γ at 100 ng/mL up-regulated COX-2 and IDO1 in HL-60 AML cells, both at mRNA and protein level. The increased COX-2 and IDO1 expression correlated with heightened production of prostaglandin (PG)E₂ and kynurenines, respectively. Nimesulide, a preferential COX-2 inhibitor, down-regulated IDO1 mRNA/protein and attenuated kynurenine synthesis, suggesting that overall IDO inhibition resulted both from reduced IDO1 gene transcription and from inhibited IDO1 catalytic activity. From a functional standpoint, IFN-g-challenged HL-60 cells promoted the in vitro conversion of allogeneic CD4⁺CD25⁻ T cells into bona fide CD4⁺CD25⁺FoxP3⁺ regulatory T cells, an effect that was significantly reduced by treatment of IFN-γ-activated HL-60 cells with nimesulide. Overall, these data point to COX-2 inhibition as a potential strategy to be pursued with the aim at circumventing leukaemia-induced, IDO-mediated immune dysfunction.
authors: Department of Haematology, Catholic University Medical School, Largo A. Gemelli 8, 00168 Rome, Italy.
authors: Maria Grazia
authors: MG
authors: Iachininoto
authors: Eugenia Rosa
authors: ER
authors: Nuzzolo
authors: Giuseppina
authors: G
authors: Bonanno
authors: Andrea
authors: A
authors: Mariotti
authors: Annabella
authors: A
authors: Procoli
authors: Franco
authors: F
authors: Locatelli
authors: Raimondo
authors: R
authors: De Cristofaro
authors: Sergio
authors: S
authors: Rutella
mesh_terms: D018920:Coculture Techniques; D051546:Cyclooxygenase 2 / Q000235:genetics / Q000378:metabolism*; D052246:Cyclooxygenase 2 Inhibitors / Q000494:pharmacology*; D015232:Dinoprostone / Q000096:biosynthesis / Q000378:metabolism; D004790:Enzyme Induction / Q000187:drug effects; D018922:HL-60 Cells; D006801:Humans; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase / Q000235:genetics / Q000378:metabolism*; D007371:Interferon-gamma / Q000502:physiology; D007737:Kynurenine / Q000096:biosynthesis; D015470:Leukemia, Myeloid, Acute; D017471:Receptors, Interferon / Q000378:metabolism; D013449:Sulfonamides / Q000494:pharmacology*; D050378:T-Lymphocytes, Regulatory / Q000276:immunology / Q000378:metabolism; D000096743:Interferon gamma Receptor
chemical_list: D051546:Cyclooxygenase 2; D052246:Cyclooxygenase 2 Inhibitors; D015232:Dinoprostone; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase; D007371:Interferon-gamma; D007737:Kynurenine; D017471:Receptors, Interferon; D013449:Sulfonamides; D000096743:Interferon gamma Receptor; C576710:IDO1 protein, human; C573415:IFNG protein, human; C496540:PTGS2 protein, human; C012655:nimesulide
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