Cargando…

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

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....

Descripción completa

Detalles Bibliográficos
Autores principales: Iachininoto, Maria Grazia, Nuzzolo, Eugenia Rosa, Bonanno, Giuseppina, Mariotti, Andrea, Procoli, Annabella, Locatelli, Franco, Cristofaro, Raimondo De, Rutella, Sergio
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2013
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6270179/
https://www.ncbi.nlm.nih.gov/pubmed/23973990
http://dx.doi.org/10.3390/molecules180910132
_version_ 1783376638181900288
author Iachininoto, Maria Grazia
Nuzzolo, Eugenia Rosa
Bonanno, Giuseppina
Mariotti, Andrea
Procoli, Annabella
Locatelli, Franco
Cristofaro, Raimondo De
Rutella, Sergio
author_facet Iachininoto, Maria Grazia
Nuzzolo, Eugenia Rosa
Bonanno, Giuseppina
Mariotti, Andrea
Procoli, Annabella
Locatelli, Franco
Cristofaro, Raimondo De
Rutella, Sergio
author_sort Iachininoto, Maria Grazia
collection PubMed
description 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)E(2) 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.
format Online
Article
Text
id pubmed-6270179
institution National Center for Biotechnology Information
language English
publishDate 2013
publisher MDPI
record_format MEDLINE/PubMed
spelling pubmed-62701792018-12-18 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 Cristofaro, Raimondo De Rutella, Sergio Molecules Article 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)E(2) 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. MDPI 2013-08-22 /pmc/articles/PMC6270179/ /pubmed/23973990 http://dx.doi.org/10.3390/molecules180910132 Text en © 2013 by the authors; licensee MDPI, Basel, Switzerland. http://creativecommons.org/licenses/by/3.0/ This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution license (http://creativecommons.org/licenses/by/3.0/).
spellingShingle Article
Iachininoto, Maria Grazia
Nuzzolo, Eugenia Rosa
Bonanno, Giuseppina
Mariotti, Andrea
Procoli, Annabella
Locatelli, Franco
Cristofaro, Raimondo De
Rutella, Sergio
Cyclooxygenase-2 (COX-2) Inhibition Constrains Indoleamine 2,3-Dioxygenase 1 (IDO1) Activity in Acute Myeloid Leukaemia Cells
title Cyclooxygenase-2 (COX-2) Inhibition Constrains Indoleamine 2,3-Dioxygenase 1 (IDO1) Activity in Acute Myeloid Leukaemia Cells
title_full Cyclooxygenase-2 (COX-2) Inhibition Constrains Indoleamine 2,3-Dioxygenase 1 (IDO1) Activity in Acute Myeloid Leukaemia Cells
title_fullStr Cyclooxygenase-2 (COX-2) Inhibition Constrains Indoleamine 2,3-Dioxygenase 1 (IDO1) Activity in Acute Myeloid Leukaemia Cells
title_full_unstemmed Cyclooxygenase-2 (COX-2) Inhibition Constrains Indoleamine 2,3-Dioxygenase 1 (IDO1) Activity in Acute Myeloid Leukaemia Cells
title_short Cyclooxygenase-2 (COX-2) Inhibition Constrains Indoleamine 2,3-Dioxygenase 1 (IDO1) Activity in Acute Myeloid Leukaemia Cells
title_sort cyclooxygenase-2 (cox-2) inhibition constrains indoleamine 2,3-dioxygenase 1 (ido1) activity in acute myeloid leukaemia cells
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6270179/
https://www.ncbi.nlm.nih.gov/pubmed/23973990
http://dx.doi.org/10.3390/molecules180910132
work_keys_str_mv AT iachininotomariagrazia cyclooxygenase2cox2inhibitionconstrainsindoleamine23dioxygenase1ido1activityinacutemyeloidleukaemiacells
AT nuzzoloeugeniarosa cyclooxygenase2cox2inhibitionconstrainsindoleamine23dioxygenase1ido1activityinacutemyeloidleukaemiacells
AT bonannogiuseppina cyclooxygenase2cox2inhibitionconstrainsindoleamine23dioxygenase1ido1activityinacutemyeloidleukaemiacells
AT mariottiandrea cyclooxygenase2cox2inhibitionconstrainsindoleamine23dioxygenase1ido1activityinacutemyeloidleukaemiacells
AT procoliannabella cyclooxygenase2cox2inhibitionconstrainsindoleamine23dioxygenase1ido1activityinacutemyeloidleukaemiacells
AT locatellifranco cyclooxygenase2cox2inhibitionconstrainsindoleamine23dioxygenase1ido1activityinacutemyeloidleukaemiacells
AT cristofaroraimondode cyclooxygenase2cox2inhibitionconstrainsindoleamine23dioxygenase1ido1activityinacutemyeloidleukaemiacells
AT rutellasergio cyclooxygenase2cox2inhibitionconstrainsindoleamine23dioxygenase1ido1activityinacutemyeloidleukaemiacells