Inhibitory effects of mitochondrial metabolic inhibitors on interferon action.

The expression of the antiviral action of the human interferons (IFNs) HuIFN-alpha and HuIFN-gamma was inhibited in human cells treated with antimetabolites affecting different mitochondrial functions. We confirmed earlier observations that cycloheximide, a specific inhibitor of cytoplasmic protein synthesis, failed to inhibit IFN action completely. Chloramphenicol, which inhibits mitochondrial protein synthesis, suppressed IFN effect when present in high concentration; in human foreskin cells, the inhibitory effect on HuIFN-alpha activity of 500 micrograms/ml chloramphenicol (which caused only 20% inhibition of overall cellular protein synthesis) was greater than that observed with 25 micrograms/ml cycloheximide (which caused 98% inhibition of overall cellular protein synthesis). Cycloheximide combined with chloramphenicol further inhibited the antiviral effect of IFN than that observed by either drug alone. Similar observations were made with mouse IFN-alpha/beta in mouse L cells. Treatment with cycloheximide, in combination with oligomycin, an inhibitor of oxidative phosphorylation, also produced an inhibition of the antiviral effect. Oligomycin, dinitrophenol, and 1799, a fluorinated uncoupler of oxidative phosphorylation, all produced IFN-suppressive effects in heteroploid human cells. These data indicate that intact mitochondrial functions are required for the full expression of the antiviral actions of IFN-alpha and IFN-gamma.