CONSTITUTIVE ACTIVATION OF U937 PROMONOCYTIC CELL CLONES SELECTED FORTHEIR RESISTANCE TO PARVOVIRUS H-1 INFECTION

The human promonocytic cell line U937 is highly sensitive to the lytic effect of the autonomous parvovirus H-1. Rare cell variants that resi sted H-1 virus infection could be isolated, of which four (RU1, RU2, R U3, and RU4) were further characterized. In contrast to parental cells , the RU clones sustained an abortive H-1 virus infection. Three of th e clones showed a significant decrease in the accumulation levels of t he c-Myc oncoprotein and in their capacity for forming tumors in immun odeficient 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 t he TPA-induced changes in membrane surface antigens and nonspecific es terase 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) an d superoxide anion (O-2(-)). Inhibitors of NO and O-2(-) production se nsitized all RU cells to the killing effect of parvovirus H-1 and incr eased the production of infectious viral particles. These data argue f or the participation of active oxygen species in macrophage defence me chanisms against parvovirus infection. Moreover, the use of parvovirus H-1 as a selective agent in a cell-colony formation assay allowed us to show that expression of defined markers of monocytic differentiatio n can be uncoupled from suppression of proliferation. (C) 1997 by The American Society of Hematology.