title: The interplay between indoleamine 2,3-dioxygenase 1 (IDO1) and cyclooxygenase (COX)-2 in chronic inflammation and cancer.
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.
authors.affiliation: IRCCS San Raffaele Pisana, Rome, Italy.
authors.forename: A
authors.initials: A
authors.lastname: Cesario
authors.forename: B
authors.initials: B
authors.lastname: Rocca
authors.forename: S
authors.initials: S
authors.lastname: Rutella
mesh_terms: D000818:Animals; D051546:Cyclooxygenase 2 / Q000276:immunology*; D052246:Cyclooxygenase 2 Inhibitors / Q000627:therapeutic use; D006801:Humans; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase / Q000276:immunology*; D007249:Inflammation / Q000188:drug therapy / Q000201:enzymology / Q000276:immunology*; D009369:Neoplasms / Q000188:drug therapy / Q000201:enzymology / Q000276:immunology*
chemical_list: D052246:Cyclooxygenase 2 Inhibitors; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase; D051546:Cyclooxygenase 2