Irradiation increases manganese superoxide dismutase mRNA levels in human fibroblasts. Possible mechanisms for its accumulation.

Irradiation induces the production of superoxide radicals (O2.-), which play an important causative role in radiation damage. Manganese superoxide dismutase (MnSOD) is a mitochondrial enzyme involved in scavenging O2..-. This study examined MnSOD gene regulation by irradiation in WI38 human fibroblasts. Unstimulated fibroblasts constitutively expressed MnSOD activity and mRNA; irradiation markedly increased MnSOD activity and mRNA levels. The increase in MnSOD transcripts by irradiation was both time- and dose-dependent. WI38 fibroblasts constitutively produce low levels of interleukin-1 (IL-1). The induction of MnSOD mRNA by irradiation was partially blocked by anti-IL-1 antibodies, and treatment of cells with IL-1 also increased MnSOD mRNA levels. Inhibition of the cyclo-oxygenase pathway with indomethacin augmented the induction MnSOD mRNA by irradiation and prostaglandin E2 inhibited the accumulation of MnSOD mRNA by irradiation. Transcriptional run-on analysis showed that irradiation increased the rate of MnSOD transcription 2-fold. Stability studies of MnSOD mRNA in these cells showed that the half-life increased from < 1.5 h in unirradiated cells to > 4 h in irradiated cells. These results suggest that induction of the MnSOD gene after irradiation is regulated, at least in part, by IL-1 production and that increased levels of MnSOD transcripts also occur through a pathway of endogenous prostaglandin E2 production. Our data indicate that the increase in MnSOD mRNA observed after irradiation occurs through both transcriptional and post-transcriptional mechanisms.