INDUCTION OF PROGRAMMED CELL-DEATH BY PARVOVIRUS H-1 IN U937 CELLS - CONNECTION WITH THE TUMOR-NECROSIS-FACTOR-ALPHA SIGNALING PATHWAY

The human promonocytic cell line U937 undergoes apoptosis upon treatme nt with tumor necrosis factor alpha (TNF-alpha), This cell line has pr eviously been shown to be very sensitive to the lytic effect of the au tonomous parvovirus H-1, Parvovirus infection leads to the activation of the CPP32 ICE-like cysteine protease which cleaves the enzyme poly( ADP-ribose)polymerase and induces morphologic changes that are charact eristic of apoptosis in away that is similar to TNF-alpha treatment. T his effect is also observed when the U937 cells are infected with a re combinant H-1 virus which expresses the nonstructural (NS) proteins bu t in which the capsid genes are replaced by a reporter gene, indicatin g that the induction of apoptosis can be assigned to the cytotoxic non structural proteins in this cell system. The c-Myc protein, which is o verexpressed in U937 cells, is rapidly downregulated during infection, in keeping with a possible role of this product in mediating the apop totic cell death induced by H-1 virus infection. Interestingly, four c lones (designated RU) derived from the U937 cell line and selected for their resistance to H-1 virus (J, A. Lopez-Guerrero et al,, Blood 89: 1642-1653, 1997) failed to decrease c-Myc expression upon treatment wi th differentiation agents and also resisted the induction of cell deat h after TNF-alpha treatment. Our data suggest that the RU clones have developed defense strategies against apoptosis, either by their failur e to downregulate c-Myc and/or by activating antiapoptotic factors.