Molecules 2013, 18(9), 10132-10145; doi:10.3390/molecules180910132
Article

Cyclooxygenase-2 (COX-2) Inhibition Constrains Indoleamine 2,3-Dioxygenase 1 (IDO1) Activity in Acute Myeloid Leukaemia Cells

1,†email, 1,†email, 2email, 2email, 2email, 3,4email, 5email and 3,* email
Received: 4 July 2013; in revised form: 14 August 2013 / Accepted: 15 August 2013 / Published: 22 August 2013
(This article belongs to the Special Issue Anti-Inflammatory & Anti-Allergy Agents in Medicinal Chemistry)
This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
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.
Keywords: indoleamine 2-3-dioxygenase; immune tolerance; acute leukaemia; regulatory T cells; immunotherapy; interferon-γ
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MDPI and ACS Style

Iachininoto, M.G.; Nuzzolo, E.R.; Bonanno, G.; Mariotti, A.; Procoli, A.; Locatelli, F.; Cristofaro, R.D.; Rutella, S. Cyclooxygenase-2 (COX-2) Inhibition Constrains Indoleamine 2,3-Dioxygenase 1 (IDO1) Activity in Acute Myeloid Leukaemia Cells. Molecules 2013, 18, 10132-10145.

AMA Style

Iachininoto MG, Nuzzolo ER, Bonanno G, Mariotti A, Procoli A, Locatelli F, Cristofaro RD, Rutella S. Cyclooxygenase-2 (COX-2) Inhibition Constrains Indoleamine 2,3-Dioxygenase 1 (IDO1) Activity in Acute Myeloid Leukaemia Cells. Molecules. 2013; 18(9):10132-10145.

Chicago/Turabian Style

Iachininoto, Maria G.; Nuzzolo, Eugenia R.; Bonanno, Giuseppina; Mariotti, Andrea; Procoli, Annabella; Locatelli, Franco; Cristofaro, Raimondo D.; Rutella, Sergio. 2013. "Cyclooxygenase-2 (COX-2) Inhibition Constrains Indoleamine 2,3-Dioxygenase 1 (IDO1) Activity in Acute Myeloid Leukaemia Cells." Molecules 18, no. 9: 10132-10145.

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