Establishment of the interferon-mediated antiviral state: possible role of superoxide dismutase.

Abstract

Superoxide dismutase (SOD; superoxide: superoxide oxidoreductase, EC 1.15.1.1) catalyzes the dismutation of O2- free radicals formed during various enzymatic reactions or by ionizing radiation. Genes coding for SOD and sensitivity to exogenous interferon (IF) are syntenic in mouse and man. Diethyldithiocarbamate (DDC) inhibits SOD activity by chelating Cu2+, the metal ion essential for the catalytic activity of the enzyme. Mouse fibroblast cell lines L and L929, IF-sensitive L1210 S6 and IF-resistant L1210 R3 leukemia cells, and a human amnion cell line (WISH) pretreated with homologous IF and different concentrations of DDC for various periods of time were tested for their ability to support vesicular stomatitis virus multiplication. Treatment of cells with DDC resulted in dose- and time-dependent inhibition of SOD activity and, simultaneously, in the reduction of antiviral protection by exogenous IF. Cells pretreated for 4 h with DDC and then washed thoroughly were also resistant to IF, but DDC was without effect if the IF effect was first established by a 4 h exposure to IF before addition of DDC. Under the conditions employed, DDC treatment did not result in any detectable inhibition of DNA, RNA or protein synthesis in these cells. SOD or a related Cu2+-requiring enzyme may be necessary for the establishment of the IF-induced antiviral state in human and murine cells.