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-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.
Highlights
Indoleamine 2,3-dioxygenase 1 (IDO1) has become a recognized mediator of immune tolerance in cancer-bearing hosts, promoting local metabolic changes that affect cellular and systemic responses to inflammatory and immunological signals [1]
Cells were analyzed by flow cytometry after labelling with anti-CD119 monoclonal antibodies that react against the IFN- receptor α chain, required for ligand binding and for signalling [28]
When providing the mixed tumour- lymphocyte culture (MTLC) with HL-60 leukaemia cells that were previously treated with NS398, Treg differentiation was inhibited, at variance with co-cultures containing acute myeloid leukaemia (AML) cells that were maintained with preferential COX-1 inhibitors, such as SC560, or with sulfone sulfide
Summary
Indoleamine 2,3-dioxygenase 1 (IDO1) has become a recognized mediator of immune tolerance in cancer-bearing hosts, promoting local metabolic changes that affect cellular and systemic responses to inflammatory and immunological signals [1]. COX-2 is constitutively over-expressed by epithelial malignancies, including human non-small cell lung cancer, where it confers a malignant and metastatic phenotype [19] This phenomenon is largely due to overproduction of PGE2, a prostanoid that enhances cell proliferation, invasion, metastasis and angiogenesis, and inhibits apoptosis [20,21,22]. The interplay between COX-2 and IDO1 is further underpinned by studies in animal models of cancer, where pharmacological blockade of COX-2 translated into down-regulation of IDO1 expression at the tumour site, leading to decreased serum kynurenines [25,26]. IFN- -induced COX-2 may regulate IDO1 expression in human leukaemia cells
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