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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,†
,
1,†
,
2
,
2
,
2
,
3,4
,
5
 and
3,*
1 Department of Haematology, Catholic University Medical School, Largo A. Gemelli 8, 00168 Rome, Italy 2 Department of Gynaecology and Obstetrics, Catholic University Medical School, Largo A. Gemelli 8, 00168 Rome, Italy 3 Department of Pediatric Haematology/Oncology and Transfusion Medicine, IRCCS Bambino Gesù Children's Hospital, Piazza Sant'Onofrio 4, 00165 Rome, Italy 4 Department of Pediatrics, University of Pavia, Strada Nuova 65, 27100 Pavia, Italy 5 Department of Medicine and Geriatrics, Catholic University Medical School, Largo A. Gemelli 8, 00168 Rome, Italy These authors contributed equally to this work.
* Author to whom correspondence should be addressed.
Received: 4 July 2013 / Revised: 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)
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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 indoleamine 2-3-dioxygenase; immune tolerance; acute leukaemia; regulatory T cells; immunotherapy; interferon-γ
This is an open access article distributed under the Creative Commons Attribution License (CC BY 3.0).
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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.

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