IFN-alpha enhances TNF-alpha-induced apoptosis through down-regulation of c-Myc protein expression in HL-60 cells.
We examined the effect of interferon-alpha (IFN-alpha) in combination with tumor necrosis factor-a (TNF-alpha) on growth, differentiation and apoptosis in HL-60 human myeloid leukemia cells. IFN-alpha inhibited cell growth and induced apoptosis, but not differentiation, in HL-60 cells. IFN-alpha enhanced TNF-alpha-induced apoptosis. We also investigated the expression of c-Myc and Bcl-2 oncoproteins, which are implicated in the survival or death of a cell. The levels of c-Myc protein expression were not changed by IFN-alpha alone at 24hrs of treatment, but were down-regulated at 72 hrs, accompanied by the appearance of apoptotic cells. While, IFN-alpha did not affect the level of Bcl-2 protein expression during this cultivation time. Interestingly, a combination treatment of IFN-alpha with TNF-alpha showed a greater decrease of c-Myc expression than TNF-a alone at 24hrs. Whereas, IFN-alpha did not significantly modulate Bcl-2 expression levels which were down-regulated by TNF-alpha. Therefore, the enhancement of TNF-alpha-induced apoptosis by IFN-a might be closely associated with the greater down-regulation of c-Myc protein, rather than Bcl-2. In contrast, with rapid down-regulation of c-Myc expression caused by TNF-alpha, IFN-alpha down-regulated c-Myc rather late (at 72 hrs), suggesting that both cytokines have a distinct pathway regulating c-Myc protein expression. However, the enhancement of apoptosis in the combination treatment would suggest the presence of a common signaling pathway for induction of apoptosis at down-stream of c-Myc.
Nakashima
A
A
Dept. of Neurology, Hematology & Rheumatology, University Hospital School of Medicine, Shimane University Izumo, Japan.
Kumakura
S
S
Mishima
S
S
Ishikura
H
H
Kobayashi
S
S
D017209:Apoptosis / Q000187:drug effects*; D002454:Cell Differentiation / Q000187:drug effects; D004273:DNA, Neoplasm / Q000378:metabolism; D015536:Down-Regulation / Q000187:drug effects*; D005434:Flow Cytometry; D018922:HL-60 Cells; D006801:Humans; D016898:Interferon-alpha / Q000494:pharmacology*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D016271:Proto-Oncogene Proteins c-myc / Q000378:metabolism*; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*
D004273:DNA, Neoplasm; D016898:Interferon-alpha; D019253:Proto-Oncogene Proteins c-bcl-2; D016271:Proto-Oncogene Proteins c-myc; D014409:Tumor Necrosis Factor-alpha