Manganous superoxide dismutase (MnSOD) scavenges potentially toxic superoxide radicals produced in the mitochondria. Tumor necrosis factor-alpha (TNF-alpha) was found to induce the messenger RNA for MnSOD, but not the mRNAs for other antioxidant or mitochondrial enzymes tested. The increase in MnSOD mRNA occurred rapidly and was blocked by actinomycin D, but not by cycloheximide. Induction of MnSOD mRNA was also observed with TNF-beta, interleukin-1 alpha (IL-1 alpha), and IL-1 beta but not with other cytokines or agents tested. TNF-alpha induced MnSOD mRNA in all cell lines and normal cells examined in vitro and in various organs of mice in vivo. These effects of TNF-alpha and IL-1 on target cells may contribute to their reported protective activity against radiation as well as their ability to induce resistance to cell killing induced by the combination of TNF-alpha and cycloheximide.