Analysis of Thymidine phosphorylase- Uridine phosphorylase double knockout mice

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Thymidine phosphorylase (TP) is an enzyme involved in the reversible conversion of thymidine to thymine. In cancer patients and tumor-bearing animals, plasma TP level is elevated, and its expression in various solid tumors is higher than in the adjacent non-neoplastic tissues. Both TP itself and the degradation product of thymidine, 2-deoxy-D-ribose, had chemotactic and angiogenic activities, and the enzymatic activity of TP was required for its angiogenic activity. TP was expressed mainly at the invasive edges of tumors and TP expression was associated with the extent of invasion of gastric and colorectal carcinoma.TP expression was also elevated in chronically inflamed tissues. TNF alpha and IFN gamma are reported to induce TP expression. To confirm the physiological role of TP, we generated mice deficient in TP gene (TPKO). TPKO mice showed an increased resistance to infection by Listeria monocytogenes. Splenic and hepatic bacterial loads 3 days after inoculation were decreased about 1 logs in TPKO. TPKO mice displays increase Interferon gamma level in plasma whereas less level of IL-10. The liver cells and spleen cells were obtained from infected mice, and cultured. The IL-10 levels in the conditioned media of the cells from TPKO mice were significantly less than those from wild-type mice. IL-10 is known to be a potent anti-inflammatory cytokine, and is suggested to reduce the function of tumor infiltrating lymphocytes and contributes the tumor growth. Therefore, we tried to test the role of TP in the escape of tumors from immune systems. Age and sex matched mice (wild-type and TP-/-) were injected i.p. with 1x10^6 of EL-4 cells. Two week after the challenge with EL-4 cells, the increase in volumes of ascites and the growth of EL-4 cells are significantly less in TPKO mice than in wild-type mice. Thus, TP may allow the escape of tumors from immune destruction and contribute the tumor growth.