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

Maria Grazia Iachininoto, Eugenia Rosa Nuzzolo, Giuseppina Bonanno, Andrea Mariotti, Annabella Procoli, Franco Locatelli, Raimondo De Cristofaro, Sergio Rutella

Research output: Contribution to journalArticle

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-?-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-?-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.

Original languageEnglish
Pages (from-to)10132-10145
Number of pages14
JournalMolecules
Volume18
Issue number9
DOIs
Publication statusPublished - Sep 2013

Keywords

  • Acute leukaemia
  • Immune tolerance
  • Immunotherapy
  • Indoleamine 2-3-dioxygenase
  • Interferon-γ
  • Regulatory T cells

ASJC Scopus subject areas

  • Organic Chemistry
  • Medicine(all)

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  • Cite this

    Iachininoto, M. G., Nuzzolo, E. R., Bonanno, G., Mariotti, A., Procoli, A., Locatelli, F., De Cristofaro, R., & Rutella, S. (2013). Cyclooxygenase-2 (COX-2) inhibition constrains indoleamine 2,3-dioxygenase 1 (IDO1) activity in acute myeloid leukaemia cells. Molecules, 18(9), 10132-10145. https://doi.org/10.3390/molecules180910132