DOWN-REGULATION OF C-MYC EXPRESSION BY TUMOR-NECROSIS-FACTOR-ALPHA IN COMBINATION WITH TRANSFORMING GROWTH-FACTOR-BETA OR INTERFERON-GAMMA WITH CONCOMITANT INHIBITION OF PROLIFERATION IN HUMAN CELL-LINES

The modulation of cell growth by tumor necrosis factor-alpha (TNF-alpha), or TNF-alpha in combination with transforming growth factor-beta (TGF-beta) or interferon-gamma (IFN-gamma) was investigated. TNF-alpha inhibited the proliferation of U937 cells, a monocytic leukemic cell line, and of NA cells that were established from oral squamous cell carcinoma. TNF-alpha showed a cytolytic effect on NA cells in the presence of actinomycin D. TNF-alpha in combination with TGF-beta and TNF-alpha combined with INF-gamma synergistically inhibited the cell proliferation of U937 and NA cells, respectively. TNF-alpha dose-dependently reduced c-myc mRNA expression of U937 and NA cells within 1 h. The combination of TNF-alpha and TGF-beta in U937 cells and that of TNF-alpha and IFN-gamma in NA cells cooperatively reduced the expression of c-myc mRNA. TNF-alpha 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-alpha action was independent of de novo protein synthesis. These data suggest that the reduction of c-myc gene at transcriptional level by TNF-alpha or TNF-alpha in combination with TGF-beta or IFN-gamma plays a primary role in the inhibition of sell growth at an early stage.