Expression of the Angiogenic Factor Thymidine Phosphorylase in THP-1 Monocytes: Induction by Autocrine Tumor Necrosis Factor-α and Inhibition by Aspirin

Abstract

The angiogenic factor thymidine phosphorylase (TP) is highly expressed in human monocytes and macrophages, and its expression has been linked to the pathology and progression of solid tumors, rheumatoid arthritis, and gastric ulcers. In this study, TP mRNA and enzyme activity were found to be upregulated upon the induction of differentiation of the human monocyte cell line THP-1 by phorbol 12-myristate 13-acetate (PMA). TP expression in THP-1 cells was similarly increased by tumor necrosis factor-␣ (TNF␣). Because monocytes and macrophages are a predominant source of TNF␣, the up-regulation of TP upon THP-1 differentiation could have been caused by the autocrine production of TNF␣. In support of this hypothesis, PMA increased TNF␣ mRNA levels; furthermore, the increase in TP expression with PMA treatment was partially blocked by a neutralizing antibody to TNF␣, particularly at the earlier time points. This data also suggested there may be additional mechanisms regulating TP expression upon PMA treatment of the cells. The induction of TP by TNF␣ was mimicked by an antibody to the TNF␣ receptor R2 (TNF-R2; p75), but not by an antibody to TNF-R1 (p55), suggesting that the TNF-R2 plays a role in the regulation of TP expression. The PMA-induced increase in TP expression was blocked by aspirin but not by the related agent indomethacin, suggesting that aspirin's effect was not caused by the inhibition of cellular cyclooxygenases. An alternative mechanism by which aspirin inhibits gene expression is the modulation of the transcription factor NFB, and the TNF␣-induced increase in TP mRNA was blocked by a cell-permeable NFB inhibitory peptide. Furthermore, TNF␣ increased and aspirin (but not indomethacin) decreased NFB DNA-binding activity in THP-1 cells. In conclusion, the modulation of TP expression in monocytes by pro-and anti-inflammatory agents suggests that its angiogenic-related actions could contribute to the inflammatory response associated with a number of pathophysiological conditions.

Inflammation and Colorectal Cancer: Does Aspirin Affect the Interaction between Cancer and Immune Cells?

“…This action could be expressed either by inhibition of angiogenic factors existing in immune cells, or by blocking their cyclooxygenase production. According to Zhu et al [14] aspirin modulates the expression of thymidine phosphoryllation in human monocytes and macrophages by increasing the production of TNFα which is an essential angiogenic agent. Therefore, the drug may play an important role in prevention of tumor development and spreading.…”

Thymidine Phosphorylase Participates in Platelet Signaling and Promotes Thrombosis

“…This hypothesis is also supported by a recent study, in which perfusion of erythrocyte-encapsulated TYMP to mice resulted in thrombi in the lungs 42 . Interestingly, Aspirin, an anti-platelet drug, inhibits TYMP production in a human monocyte cell line, THP1 cells 43 , suggesting that Aspirin may also inhibit TYMP production in platelet and thus results in the anti-thrombotic effect. We found that TYMP deficiency did not affect expression of GPIb, GPVI (not shown), von Willebrand Factor or integrin β 1 and β 3 expression in platelets nor was the number of circulating platelets or their mitochondrial function affected by the loss of TYMP.…”

5′-O-Tritylated Nucleoside Derivatives: Inhibition of Thymidine Phosphorylase and Angiogenesis

“…Besides tumor cells, also lymphocytes, fibroblasts, and tumor-infiltrating macrophages were found to express elevated levels of TPase (Sivridis et al, 2002;Akiyama et al, 2004;Toi et al, 2005). In fact, macrophages are known to produce multiple angiogenesis mediators, including cytokines that may up-regulate TPase transcription and enzyme activity, such as tumor necrosis factor-␣, interleukin-1, interferon-␥, and interferon-␣ (Goto et al, 2001;Zhu and Schwartz, 2003;De Bruin et al, 2004;Yao et al, 2005). In addition, hypoxia, low pH, and chemotherapeutic agents, including cyclophosphamide, oxaliplatin and taxanes, and X-ray radiation have been shown to increase TPase/PD-ECGF protein levels in various human tumors (Griffiths et al, 1997;Sawada et al, 1999;Kikuno et al, 2004, Toi et al, 2004.…”