p38-mediated regulation of an Fas-associated death domain protein-independent pathway leading to caspase-8 activation during TGF beta-induced apoptosis in human Burkitt lymphoma B cells BL41

On binding to its receptor, transforming growth factor beta (TGF beta) indu ces apoptosis. in a variety of cells, including human B lymphocytes. We hav e previously reported that TGF beta -mediated apoptosis is caspase-dependen t and associated with activation of caspase-3. We show here that caspase-8 inhibitors strongly decrease TGF beta -mediated apoptosis. in BL41 Burkitt' s lymphoma cells. These inhibitors act upstream of the mitochondria because they inhibited the loss of mitochondrial membrane potential observed in TG F beta -treated cells. TGF beta induced caspase-8 activation in these cells as shown by the cleavage of specific substrates, including Bid, and the ap pearance of cleaved fragments of caspase-8. Our data show that TGFP induces an apoptotic. pathway involving sequential caspase-8 activation, loss of m itochondrial membrane potential, and caspase-9 and -3 activation. Caspase-8 activation was Fas-associated death domain protein (FADD)-independent beca use cells expressing a dominant negative mutant of FADD were still sensitiv e to TGF beta -induced caspase-8 activation and apoptosis. This FADD-indepe ndent pathway of caspase-8 activation is regulated by p38. Indeed, TGF beta -induced activation of p38 and two different inhibitors specific for this mitogen-activated protein kinase pathway (SB203580 and PD169316) prevented TGF beta -mediated caspase-8 activation as well as the loss of mitochondria l membrane potential and apoptosis. Overall, our data show that p38 activat ion by TGF beta induced an apoptotic pathway via FADD-independent activatio n of caspase-8.