Cyclooxygenase-2 (COX-2) inhibition constrains indoleamine 2,3-dioxygenase 1 (IDO1) activity in acute myeloid leukaemia cells

Iachininoto, M., Nuzzolo, E., Bonanno, G., Mariotti, A., Procoli, A., Locatelli, F., Cristofaro, R. and Rutella, S. ORCID: 0000-0003-1970-7375, 2013. Cyclooxygenase-2 (COX-2) inhibition constrains indoleamine 2,3-dioxygenase 1 (IDO1) activity in acute myeloid leukaemia cells. Molecules, 18 (9), pp. 10132-10145. ISSN 1420-3049

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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.

Item Type: Journal article
Publication Title: Molecules
Creators: Iachininoto, M., Nuzzolo, E., Bonanno, G., Mariotti, A., Procoli, A., Locatelli, F., Cristofaro, R. and Rutella, S.
Publisher: MDPI
Date: 22 August 2013
Volume: 18
Number: 9
ISSN: 1420-3049
Identifiers:
NumberType
10.3390/molecules180910132DOI
Divisions: Schools > School of Science and Technology
Depositing User: Jonathan Gallacher
Date Added: 12 Sep 2016 08:50
Last Modified: 13 Oct 2017 13:33
URI: http://irep.ntu.ac.uk/id/eprint/28441

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