Downregulation 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 cell growth at an early stage.
Hori
M
M
Second Department of Oral and Maxillofacial Surgery, School of Dentistry, Showa University, Tokyo, Japan.
Kamijo
R
R
Takeda
K
K
Nagumo
M
M
D002455:Cell Division / Q000276:immunology; D003513:Cycloheximide / Q000494:pharmacology; D004306:Dose-Response Relationship, Immunologic; D015536:Down-Regulation / Q000187:drug effects / Q000276:immunology; D006801:Humans; D007371:Interferon-gamma / Q000276:immunology*; D009000:Monocytes / Q000276:immunology*; D016271:Proto-Oncogene Proteins c-myc / Q000096:biosynthesis*; D012333:RNA, Messenger; D011994:Recombinant Proteins; D016212:Transforming Growth Factor beta / Q000276:immunology*; D014407:Tumor Cells, Cultured; D014409:Tumor Necrosis Factor-alpha / Q000276:immunology*
D016271:Proto-Oncogene Proteins c-myc; D012333:RNA, Messenger; D011994:Recombinant Proteins; D016212:Transforming Growth Factor beta; D014409:Tumor Necrosis Factor-alpha; D007371:Interferon-gamma; D003513:Cycloheximide