Expression of the angiogenic factor thymidine phosphorylase in THP-1 monocytes: induction by autocrine tumor necrosis factor-alpha and inhibition by aspirin.
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-alpha (TNFalpha). Because monocytes and macrophages are a predominant source of TNFalpha, the up-regulation of TP upon THP-1 differentiation could have been caused by the autocrine production of TNFalpha. In support of this hypothesis, PMA increased TNFalpha mRNA levels; furthermore, the increase in TP expression with PMA treatment was partially blocked by a neutralizing antibody to TNFalpha, 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 TNFalpha was mimicked by an antibody to the TNFalpha 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 NFkappaB, and the TNFalpha-induced increase in TP mRNA was blocked by a cell-permeable NFkappaB inhibitory peptide. Furthermore, TNFalpha increased and aspirin (but not indomethacin) decreased NFkappaB 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.
Deptartment of Oncology, Albert Einstein Cancer Center, Montefiore Medical Center, 111 East 210th Street, Bronx, NY 10467, USA.
Geng Hui
GH
Zhu
Edward L
EL
Schwartz
D043925:Angiogenesis Inducing Agents / Q000378:metabolism; D000906:Antibodies / Q000494:pharmacology; D001241:Aspirin / Q000494:pharmacology*; D015870:Gene Expression / Q000187:drug effects*; D006801:Humans; D008264:Macrophages; D009000:Monocytes / Q000187:drug effects* / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism; D011506:Proteins / Q000502:physiology; D012333:RNA, Messenger / Q000187:drug effects / Q000235:genetics; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D047992:TNF Receptor-Associated Factor 2; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D013939:Thymidine Phosphorylase / Q000096:biosynthesis* / Q000235:genetics; D014409:Tumor Necrosis Factor-alpha / Q000276:immunology / Q000494:pharmacology*
D043925:Angiogenesis Inducing Agents; D000906:Antibodies; D016328:NF-kappa B; D011506:Proteins; D012333:RNA, Messenger; D047992:TNF Receptor-Associated Factor 2; D014409:Tumor Necrosis Factor-alpha; D013939:Thymidine Phosphorylase; D013755:Tetradecanoylphorbol Acetate; D001241:Aspirin