Downregulation of c-mycExpression by Tumor Necrosis Factor-α in Combination with Transforming Growth Factor-β or Interferon-γ with Concomitant Inhibition of Proliferation in Human Cell Lines

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Abstract
The modulation of cell growth by tumor necrosis factor-α (TNF-α), or TNF-α in combination with transforming growth factor-β (TGF-β) or interferon-γ (IFN-γ) was investigated. TNF-α inhibited the proliferation of U937 cells, a monocytic leukemic cell line, and of NA cells that were established from oral squamous cell carcinoma. TNF-α showed a cytolytic effect on NA cells in the presence of actinomycin D. TNF-α in combination with TGF-β and TNF-α combined with INF-γ synergistically inhibited the cell proliferation of U937 and NA cells, respectively. TNF-α dose-dependently reduced c-myc mRNA expression of U937 and NA cells within 1 h. The combination of TNF-α and TGF-β in U937 cells and that of TNF-α and IFN-γ in NA cells cooperatively reduced the expression of c-myc mRNA. TNF-α had little or no effect on the half-life of c-myc mRNA, indicating that c-myc mRNA expression was reduced at transcriptional level. Cycloheximide did not mediate the inhibition of c-myc gene expression, suggesting that the TNF-α action was independent of de novo protein synthesis. These data suggest that the reduction of c-myc gene at transcriptional level by TNF-α or TNF-α in combination with TGF-β or IFN-γ plays a primary role in the inhibition of cell growth at an early stage.