Granulocyte-macrophage colony-stimulating factor: inhibitor of tumor necrosis factor-induced apoptosis.
Tumor necrosis factor (TNF) can induce proliferation as well as apoptosis in acute myeloid leukemia (AML)-derived cells. We have shown recently that these seemingly contradictory effects are based on the divergent capacities of the cells to produce granulocyte-macrophage colony-stimulating factor (GM-CSF) upon stimulation with TNF. Only those cells that produce GM-CSF survive the TNF attack and start growing. Here, we set out to elucidate the mechanisms of the antiapoptotic effect of GM-CSF. Protection from apoptosis was achieved by preincubating TF-1 cells with exogeneous GM-CSF. Cycloheximide prevented protection, indicating that GM-CSF might induce synthesis of antiapoptotic proteins. Regulation of protective genes was analyzed using cDNA expression arrays and the results were verified by Northern and Western blot analysis. This screen revealed the elevated expression of BCL-2, BCL-2A1, BAG-1 and TACE upon stimulation with GM-CSF. The major novelty of our study is that GM-CSF carries protective effects against TNF-induced apoptosis, not only against apoptosis induced by irradiation or cytokine-starvation. This protection requires de novo protein synthesis and is not-or at least not exclusively-the consequence of a direct crosstalk between the GM-CSF and TNF signaling pathways.
Quentmeier
Hilmar
H
Department of Human and Animal Cell Cultures, DSMZ-German Collection of Microorganisms and Cell Cultures, Mascheroder Weg 1B, D-38124, Braunschweig, Germany. hqu@dsmz.de
Reinhardt
Julia
J
Zaborski
Margarete
M
Drexler
Hans G
HG
D051722:ADAM Proteins; D000072198:ADAM17 Protein; D017209:Apoptosis / Q000187:drug effects*; D015152:Blotting, Northern; D015153:Blotting, Western; D002352:Carrier Proteins / Q000378:metabolism; D003513:Cycloheximide / Q000494:pharmacology; D004268:DNA-Binding Proteins; D020869:Gene Expression Profiling; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000494:pharmacology*; D006801:Humans; D020935:MAP Kinase Signaling System / Q000187:drug effects; D008666:Metalloendopeptidases / Q000378:metabolism; D020411:Oligonucleotide Array Sequence Analysis; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D014157:Transcription Factors; D014407:Tumor Cells, Cultured / Q000187:drug effects / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors* / Q000494:pharmacology
C091732:BCL2-associated athanogene 1 protein; D002352:Carrier Proteins; D004268:DNA-Binding Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D014157:Transcription Factors; D014409:Tumor Necrosis Factor-alpha; D016178:Granulocyte-Macrophage Colony-Stimulating Factor; D003513:Cycloheximide; D051722:ADAM Proteins; D008666:Metalloendopeptidases; D000072198:ADAM17 Protein; C000606462:ADAM17 protein, human