Interferon gamma-dependent induction of thymidine phosphorylase/platelet-derived endothelial growth factor through gamma-activated sequence-like element in human macrophages.

ABSTRACT

Thymidine phosphorylase (TP), an enzyme involved in the reversible conversion of thymidine to thymine, is identical to platelet-derived endothelial cell growth factor. TP expression in cancer cells and/or infiltrated macrophages is associated with microvessel density and poor clinical prognosis in patients with various tumor types. However, how TP expression is up-regulated in human tumors is unclear. Of various inflammatory cytokines, such as tumor necrosis factor alpha (TNF-alpha), interleukin 1 alpha (IL-1alpha), and interferon gamma (IFN-gamma), we observed that IFN-gamma most effectively increased the expression of TP in cultured human monocytic U937 cells. Transient transfection of the various deletion constructs of the TP promoter showed that the presence of the -474 to -355 sequence containing gamma-activated sequence-like element was essential for IFN-gamma-dependent activation of the TP gene. Furthermore, the IFN-gamma-dependent transcriptional activity of the promoter construct containing mutations in the gamma-activated sequence-like element was significantly decreased. An electrophoretic mobility shift assay showed that IFN-gamma increased signal transducers and activators of transcription 1 binding to gamma-activated sequence-like element in the TP promoter. IFN-gamma could be a mediator of TP expression in infiltrated monocyte/macrophages, and those monocyte/macrophages expressing TP might play an important role in malignancy and angiogenesis in various human tumors.