AN ESSENTIAL ROLE FOR THE INTERFERON-INDUCIBLE, DOUBLE-STRANDED RNA-ACTIVATED PROTEIN-KINASE PKR IN THE TUMOR NECROSIS FACTOR-INDUCED APOPTOSIS IN U937 CELLS

Tumor necrosis factor alpha (TNF-alpha) is well-characterized for its necrotic action against tumor cells; however, it has been increasingly associated with an apoptosis-inducing potential on target cells, Whil e the signaling events and the actual cytolytic mechanism(s) for both TNF alpha-induced necrosis and apoptosis remain to be fully elucidated , we report here on (i) the ability of TNF-alpha to induce apoptosis i n the promonocytic U937 cells, (ii) the discovery of a cross-talk betw een the TNF-alpha and the interferon signaling pathways, and (iii) the pivotal role of interferon-inducible, double-stranded RNA-activated p rotein kinase (PKR) in the induction of apoptosis by TNF-alpha. Our da ta from microscopy studies, trypan blue exclusion staining, and apopto tic DNA ladder electrophoresis revealed that a subclone derived from U 937 and carrying a PKR antisense expression vector was resistant to TN F-alpha-induced apoptosis. Further, TNF-alpha initiated a generalized RNA degradation process in which the participation of PKR was required , Finally, the PKR gene is a candidate ''death gene'' since overexpres sion of this gene could bring about apoptosis in U937 cells.