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

Geng Hui Zhu, Edward L. Schwartz

Research output: Contribution to journalArticle

25 Scopus citations

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 up-regulated 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-α (TNFα). Because monocytes and macrophages are a predominant source of TNFα, the up-regulation of TP upon THP-1 differentiation could have been caused by the autocrine production of TNFα. In support of this hypothesis, PMA increased TNFα mRNA levels; furthermore, the increase in TP expression with PMA treatment was partially blocked by a neutralizing antibody to TNFα, 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 TNFα was mimicked by an antibody to the TNFα 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 NFκB, and the TNFα-induced increase in TP mRNA was blocked by a cell-permeable NFκB inhibitory peptide. Furthermore, TNFα increased and aspirin (but not indomethacin) decreased NFκB 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.

Original languageEnglish (US)
Pages (from-to)1251-1258
Number of pages8
JournalMolecular Pharmacology
Volume64
Issue number5
DOIs
StatePublished - Nov 1 2003

ASJC Scopus subject areas

  • Molecular Medicine
  • Pharmacology

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