Inhibition of p38 Kinase Reveals a TNF-α-Mediated, Caspase-Dependent, Apoptotic Death Pathway in a Human Myelomonocyte Cell Line
| Autor: | Souvik Chattopadhaya, Jishy Varghese, Apurva Sarin |
|---|---|
| Rok vydání: | 2001 |
| Předmět: |
Cytotoxicity
Immunologic Programmed cell death Immunology Active Transport Cell Nucleus Apoptosis BH3 interacting-domain death agonist Cysteine Proteinase Inhibitors Inhibitor of apoptosis p38 Mitogen-Activated Protein Kinases Jurkat cells Amino Acid Chloromethyl Ketones Jurkat Cells Mice Animals Humans Immunology and Allergy Myeloid Cells Cycloheximide Protein kinase A Myelomonocyte Caspase Cell Nucleus Cell Death biology Tumor Necrosis Factor-alpha Macrophages NF-kappa B U937 Cells Caspase Inhibitors Caspase 9 Cell biology Enzyme Activation Drug Combinations Gene Expression Regulation Caspases biology.protein Mitogen-Activated Protein Kinases Signal Transduction |
| Zdroj: | Scopus-Elsevier |
| ISSN: | 1550-6606 0022-1767 |
| Popis: | TNF-α transduces signals of survival or death via its two receptors, R1/p55/p60 and RII/p80/p75. The role of caspases as effectors of cell death is universally accepted, although caspase inhibitors may potentiate TNF cytotoxicity in some instances. In conditions when macromolecular synthesis is blocked, caspases are part of the machinery that executes TNF-triggered apoptotic death in U937, a human myelomonocyte cell line, and in the Jurkat T cell line. However, inhibition of p38 mitogen-activated protein kinase (p38 MAPK) triggered TNF cytotoxicity in U937 cells and murine splenic macrophages, but not the Jurkat cell line. TNF induced expression of the antiapoptotic protein c-IAP2 (cytoplasmic inhibitor of apoptosis protein 2), and was blocked in the presence of a p38 MAPK inhibitor, which also induced caspase-dependent, TNF-mediated apoptosis in U937 cells. Thus, inhibition of p38 MAPK resulted in the activation of caspase 9 and cleavage of the adaptor molecule BH3 interacting domain death agonist, and blocked NF-κB-mediated transactivation, without affecting the nuclear translocation of NF-κB. Collectively, these data show that activation of p38 MAPK is critical to cell survival by TNF in U937 cells, and demonstrate lineage-specific regulation of TNF-triggered signals of activation or apoptosis. |
| Databáze: | OpenAIRE |
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