Next Article in Journal
Sinulariolide Induced Hepatocellular Carcinoma Apoptosis through Activation of Mitochondrial-Related Apoptotic and PERK/eIF2α/ATF4/CHOP Pathway
Next Article in Special Issue
Physiological Roles and Potential Therapeutic Applications of the P2X7 Receptor in Inflammation and Pain
Previous Article in Journal
Variation of Vitamin D in Cow’s Milk and Interaction with β-Lactoglobulin
Previous Article in Special Issue
Luteolin Inhibits Inflammatory Responses via p38/MK2/TTP-mediated mRNA Stability
Molecules 2013, 18(9), 10132-10145; doi:10.3390/molecules180910132
Article

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

1,†
, 1,†
, 2
, 2
, 2
, 3,4
, 5
 and 3,*
1 Department of Haematology, Catholic University Medical School, Largo A. Gemelli 8, 00168 Rome, Italy 2 Department of Gynaecology and Obstetrics, Catholic University Medical School, Largo A. Gemelli 8, 00168 Rome, Italy 3 Department of Pediatric Haematology/Oncology and Transfusion Medicine, IRCCS Bambino Gesù Children's Hospital, Piazza Sant'Onofrio 4, 00165 Rome, Italy 4 Department of Pediatrics, University of Pavia, Strada Nuova 65, 27100 Pavia, Italy 5 Department of Medicine and Geriatrics, Catholic University Medical School, Largo A. Gemelli 8, 00168 Rome, Italy These authors contributed equally to this work.
* Author to whom correspondence should be addressed.
Received: 4 July 2013 / Revised: 14 August 2013 / Accepted: 15 August 2013 / Published: 22 August 2013
(This article belongs to the Special Issue Anti-Inflammatory & Anti-Allergy Agents in Medicinal Chemistry)
Download PDF [897 KB, uploaded 18 June 2014]

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-g-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-g-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.
Keywords: indoleamine 2-3-dioxygenase; immune tolerance; acute leukaemia; regulatory T cells; immunotherapy; interferon-γ indoleamine 2-3-dioxygenase; immune tolerance; acute leukaemia; regulatory T cells; immunotherapy; interferon-γ
This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Share & Cite This Article

Export to BibTeX |
EndNote


MDPI and ACS Style

Iachininoto, M.G.; Nuzzolo, E.R.; Bonanno, G.; Mariotti, A.; Procoli, A.; Locatelli, F.; Cristofaro, R.D.; Rutella, S. Cyclooxygenase-2 (COX-2) Inhibition Constrains Indoleamine 2,3-Dioxygenase 1 (IDO1) Activity in Acute Myeloid Leukaemia Cells. Molecules 2013, 18, 10132-10145.

View more citation formats

Related Articles

Article Metrics

Comments

Citing Articles

[Return to top]
Molecules EISSN 1420-3049 Published by MDPI AG, Basel, Switzerland RSS E-Mail Table of Contents Alert