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CD95 (Fas)-induced Caspase-mediated Proteolysis of NF-B¹

Johns Hopkins Oncology Center, Division of Experimental Therapeutics and Pharmacology, Baltimore, Maryland 21287

Activation of the nuclear factor (NF)-B transcription factor is instrumental for the immune response and the survival of peripheral activated T cells. We demonstrate that ligation of CD95 (Fas/APO1), a potent apoptotic stimulus in lymphocytes, results in repression of NF-B activity in Jurkat T cells by inducing the proteolytic cleavage of NF-B p65 (Rel A) and p50. Inhibition of caspase-3-related proteases by a specific acetylated aldehyde (Ac-DEVD-CHO) prevented CD95-induced cleavage of p65 (RelA) or p50 and restored the inducibility of NF-B in cells treated with an antibody against CD95. The addition of recombinant caspase-3 also resulted in proteolytic cleavage of RelA p65 and p50 in vitro. TNF- treatment, unlike CD95 ligation, did not result in the death of Jurkat cells but did so in the presence of IBM, a transdominant inhibitor of NF-B. These results suggest that intact, functional NF-B maintains the survival of activated T cells, and that CD95-induced cleavage of NF-B subunits sensitizes T cells to apoptosis and, hence, facilitates the decay of an immune response.

¹ This work was funded in part by Grant 1 R29CA71660-01A1 from the National Cancer Institute (to A. B.). A. B. is a recipient of a Passano Physician Scientist award, a Jose Carreras American Society of Hematology Scholar award, and grants from the American Cancer Society and the Wendy Will Case Cancer Fund.

² To whom requests for reprints should be addressed, at 3-127 Johns Hopkins Oncology Center, 600 North Wolfe Street, Baltimore, Maryland 21287. Phone: (410) 955-8797; Fax: (410) 955-1969.

Received 11/17/97. Accepted 1/19/98.

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