Constitutive activation of U937 promonocytic cell clones selected for their resistance to parvovirus H-1 infection

Abstract

The human promonocytic cell line U937 is highly sensitive to the lytic effect of the autonomous pervovirus H-1. Rare cell variants that resisted H- 1 virus infection could be isolated, of which four (RU1, RU2, RU3, and RU4) were further characterized. In contrast to parental cells, the RU clones sustained an abortive H-1 virus infection. Three of the clones showed a significant decrease in the accumulation levels of the c-Myc oncoprotein and in their capacity for forming tumors in immunodeficient mice. Surprisingly, all RU clones resisted the suppressing effect of 12-O-tetradecanoylphorbol- 13-acetate (TPA) on c-myc oncogene expression and cell proliferation. In contrast, RU clones exhibited the TPA-induced changes in membrane surface antigens and nonspecific esterase activities that are characteristic of monocytic differentiation. Studies of the activation steady-state of RU cells demonstrated the constitutive production of significant amounts of nitric oxide (NO) and superoxide anion (O2/-). Inhibitors of NO and O2/- production sensitized all RU cells to the killing effect of pervovirus H-1 and increased the production of infectious viral particles. These data argue for the participation of active oxygen species in macrophage defence mechanisms against pervovirus infection. Moreover, the use of pervovirus H-1 as a selective agent in a cellcolony formation assay allowed us to show that expression of defined markers of monocytic differentiation can be uncoupled from suppression of proliferation.