CD95 (FAS)-INDUCED CASPASE-MEDIATED PROTEOLYSIS OF NF-KAPPA-B

Activation of the nuclear factor (NF)-kappa B transcription factor is instrumental for the immune response and the survival of peripheral ac tivated T cells, We demonstrate that ligation of CD95 (Fas/APO1), a po tent apoptotic stimulus in lymphocytes, results in repression of NF-ka ppa B activity in Jurkat T cells by inducing the proteolytic cleavage of NF-kappa B p65 (Rel A) and p50. inhibition of caspase-3-related pro teases by a specific acetylated aldehyde (Ac-DEVD-CHO) prevented CD95- induced cleavage of p65 (RelA) or p50 and restored the inducibility of NF-kappa B in cells treated with an antibody against CD95, The additi on of recombinant caspase-3 also resulted in proteolytic cleavage of R eIA p65 and p50 in vitro. TNF-alpha treatment, unlike CD95 ligation, d id not result in the death of Jurkat cells but did so in the presence of I kappa B alpha M, a transdominant inhibitor of NF-kappa B. These r esults suggest that intact, functional NF-kappa B maintains the surviv al of activated T cells, and that CD95-induced cleavage of NF-kappa B subunits sensitizes T cells to apoptosis and, hence, facilitates tile decay of an immune response.