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

16 Citations (Scopus)

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

Fingerprint

Indoleamine-Pyrrole 2,3,-Dioxygenase
Myeloid Cells
Cyclooxygenase 2
Acute Myeloid Leukemia
nimesulide
Kynurenine
T-cells
Cyclooxygenase 2 Inhibitors
HL-60 Cells
T-Lymphocytes
Messenger RNA
Antigen-Presenting Cells
Regulatory T-Lymphocytes
Transcription
Dinoprostone
Tryptophan
Prostaglandins
Tumors
Catalyst activity
Leukemia

Keywords

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

ASJC Scopus subject areas

  • Organic Chemistry
  • Medicine(all)

Cite this

Cyclooxygenase-2 (COX-2) inhibition constrains indoleamine 2,3-dioxygenase 1 (IDO1) activity in acute myeloid leukaemia cells. / Iachininoto, Maria Grazia; Nuzzolo, Eugenia Rosa; Bonanno, Giuseppina; Mariotti, Andrea; Procoli, Annabella; Locatelli, Franco; De Cristofaro, Raimondo; Rutella, Sergio.

In: Molecules, Vol. 18, No. 9, 09.2013, p. 10132-10145.

Research output: Contribution to journalArticle

Iachininoto, MG, Nuzzolo, ER, 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, vol. 18, no. 9, pp. 10132-10145. https://doi.org/10.3390/molecules180910132
Iachininoto, Maria Grazia ; Nuzzolo, Eugenia Rosa ; Bonanno, Giuseppina ; Mariotti, Andrea ; Procoli, Annabella ; Locatelli, Franco ; De Cristofaro, Raimondo ; Rutella, Sergio. / Cyclooxygenase-2 (COX-2) inhibition constrains indoleamine 2,3-dioxygenase 1 (IDO1) activity in acute myeloid leukaemia cells. In: Molecules. 2013 ; Vol. 18, No. 9. pp. 10132-10145.
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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-?-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.",
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T1 - Cyclooxygenase-2 (COX-2) inhibition constrains indoleamine 2,3-dioxygenase 1 (IDO1) activity in acute myeloid leukaemia cells

AU - Iachininoto, Maria Grazia

AU - Nuzzolo, Eugenia Rosa

AU - Bonanno, Giuseppina

AU - Mariotti, Andrea

AU - Procoli, Annabella

AU - Locatelli, Franco

AU - De Cristofaro, Raimondo

AU - Rutella, Sergio

PY - 2013/9

Y1 - 2013/9

N2 - 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.

AB - 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.

KW - Acute leukaemia

KW - Immune tolerance

KW - Immunotherapy

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KW - Interferon-γ

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