P1–162 - The Role of Indoleamine 2,3-Dioxygenase in Hepatocellular Carcinoma

Abstract

Background: Indoleamine 2,3-dioxygenase (IDO) is an intracellular enzyme that catalyzes the first and rate-limiting step in the catabolism of the essential amino acid tryptophan along the kynurenine pathway. In the tumor microenvironment, increased IDO activity inhibits T cell and natural killer cell proliferation and induces apoptosis through tryptophan depletion and production of toxic tryptophan catabolites. In this study, we investigated the role of IDO in diethylnitrosamine (DEN)-induced hepatocarcinogenesis using IDO-deficient (IDO�/�) mice. Methods: To induce hepatocellular carcinoma (HCC) and preneoplastic hepatocellular lesions, foci of cellular alteration (FCA), male IDO�/� mice and their wild type (WT) male C57BL/6J mice receive a single intraperitoneal injection of DEN (25mg/kg body weight) at 2 weeks of age. The mice were sacrificed at 20 or 32 weeks of age to determine the incidence and multiplicity of FCA and hepatocellular neoplasms. Results: The numbers of FCA and HCC developed in the IDO�/� mice was significantly lower than that of the WT mice. The expression levels of Foxp3 mRNA in HCCs were significantly higher than those of their surrounding stromal tissues in both of the WT and IDO�/� mice. The expression levels of COX-2 and TNF-α mRNA in HCC developed in the IDO�/� mice were found to be significantly down-regulated when compared to the WT mice. Conclusion: IDO up-regulation contributes to the early and late phase of liver carcinogenesis. Our findings suggest that inhibition of IDO might offer a promising strategy for the prevention of HCC development.