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

Molecules

Maria Grazia Iachininoto¹  Eugenia Rosa Nuzzolo¹  Giuseppina Bonanno³  Andrea Mariotti³  Annabella Procoli³  Franco Locatelli⁴  Raimondo De Cristofaro² 

[1] Department of Haematology, Catholic University Medical School, Largo A. Gemelli 8, 00168 Rome, Italy; E-Mails:;Department of Medicine and Geriatrics, Catholic University Medical School, Largo A. Gemelli 8, 00168 Rome, Italy; E-Mail:;Department of Gynaecology and Obstetrics, Catholic University Medical School, Largo A. Gemelli 8, 00168 Rome, Italy; E-Mails:;Department of Pediatric Haematology/Oncology and Transfusion Medicine, IRCCS Bambino Gesù Children’s Hospital, Piazza Sant’Onofrio 4, 00165 Rome, Italy; E-Mail:

关键词: indoleamine 2-3-dioxygenase;    immune tolerance;    acute leukaemia;    regulatory T cells;    immunotherapy;    interferon-γ;   

DOI  :  10.3390/molecules180910132

来源: mdpi

【 摘 要 】

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-γ-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-γ-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.

【 授权许可】

CC BY   
© 2013 by the authors; licensee MDPI, Basel, Switzerland.