Abstract
The enzyme indoleamine 2,3-dioxygenase 1 (IDO1) degrades the essential amino acid tryptophan into kynurenine and other downstream metabolites that suppress effector T-cell function and favor the differentiation of regulatory T cells. IDO1 is traditionally viewed as a general suppressor of T-cell activation and mediator of immune escape in cancer. Recently, evidence has emerged to support a greater functional complexity of IDO1 as modifier of pathogenic inflammation. For instance, IDO1 activity may sustain autoantibody production by B cells, and elicit the development of cancer in the context of chronic inflammation. Cyclooxygenase (COX)-2 metabolizes the first enzymatic step in the conversion of arachidonic acid into prostanoids. In particular, prostaglandin (PG)E2 generated at sites of inflammation and/or immune response is mainly COX-2-derived and has pro-inflammatory and immune regulatory activities. Pharmacological blockade of COX-2 in animal models of cancer translates into down-regulation of IDO1 expression at tumor sites and decreased levels of kynurenine in the circulation, underpinning the view that IDO1 might be downstream of COX-2. This article reviews preclinical studies focusing on IDO1 and COX-2 as inter-related molecular targets for therapeutic intervention in chronic inflammation and cancer. COX-2 inhibition might, in principle, be pursued in cancer-associated inflammation characterized by IDO1 hyper-activity, with the foreseeable aim at altering the immune response within the tumor microenvironment.
Keywords: Indoleamine 2,3-dioxygenase, immune tolerance, regulatory T cell, hematopoietic growth factors, cancer, cyclooxygenase-2, prostaglandins, IDO1, amino acid tryptophan, kynurenine
Current Medicinal Chemistry
Title: The Interplay between Indoleamine 2,3-Dioxygenase 1 (IDO1) and Cyclooxygenase (COX)-2 In Chronic Inflammation and Cancer
Volume: 18 Issue: 15
Author(s): A. Cesario, B. Rocca and S. Rutella
Affiliation:
Keywords: Indoleamine 2,3-dioxygenase, immune tolerance, regulatory T cell, hematopoietic growth factors, cancer, cyclooxygenase-2, prostaglandins, IDO1, amino acid tryptophan, kynurenine
Abstract: The enzyme indoleamine 2,3-dioxygenase 1 (IDO1) degrades the essential amino acid tryptophan into kynurenine and other downstream metabolites that suppress effector T-cell function and favor the differentiation of regulatory T cells. IDO1 is traditionally viewed as a general suppressor of T-cell activation and mediator of immune escape in cancer. Recently, evidence has emerged to support a greater functional complexity of IDO1 as modifier of pathogenic inflammation. For instance, IDO1 activity may sustain autoantibody production by B cells, and elicit the development of cancer in the context of chronic inflammation. Cyclooxygenase (COX)-2 metabolizes the first enzymatic step in the conversion of arachidonic acid into prostanoids. In particular, prostaglandin (PG)E2 generated at sites of inflammation and/or immune response is mainly COX-2-derived and has pro-inflammatory and immune regulatory activities. Pharmacological blockade of COX-2 in animal models of cancer translates into down-regulation of IDO1 expression at tumor sites and decreased levels of kynurenine in the circulation, underpinning the view that IDO1 might be downstream of COX-2. This article reviews preclinical studies focusing on IDO1 and COX-2 as inter-related molecular targets for therapeutic intervention in chronic inflammation and cancer. COX-2 inhibition might, in principle, be pursued in cancer-associated inflammation characterized by IDO1 hyper-activity, with the foreseeable aim at altering the immune response within the tumor microenvironment.
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Cesario A., Rocca B. and Rutella S., The Interplay between Indoleamine 2,3-Dioxygenase 1 (IDO1) and Cyclooxygenase (COX)-2 In Chronic Inflammation and Cancer, Current Medicinal Chemistry 2011; 18 (15) . https://dx.doi.org/10.2174/092986711795656063
DOI https://dx.doi.org/10.2174/092986711795656063 |
Print ISSN 0929-8673 |
Publisher Name Bentham Science Publisher |
Online ISSN 1875-533X |
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