Inhibition of p38 kinase reveals a TNF-alpha-mediated, caspase-dependent, apoptotic death pathway in a human myelomonocyte cell line

TNF-alpha 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 i s universally accepted, although caspase inhibitors may potentiate TNF cyto toxicity in some instances. In conditions when macromolecular synthesis is blocked, caspases are part of the machinery that executes TNF-triggered apo ptotic 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 macropha ges, but not the Jurkat cell line. TNF induced expression of the antiapopto tic 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 M APK resulted in the activation of caspase 9 and cleavage of the adaptor mol ecule BH3 interacting domain death agonist, and blocked NF-kappaB-mediated transactivation, without affecting the nuclear translocation of NF-kappaB. Collectively, these data show that activation of p38 MAPK is critical to ce ll survival by TNF in U937 cells, and demonstrate lineage-specific regulati on of TNF-triggered signals of activation or apoptosis.