IRRADIATION INCREASES MANGANESE SUPEROXIDE-DISMUTASE MESSENGER-RNA LEVELS IN HUMAN FIBROBLASTS - POSSIBLE MECHANISMS FOR ITS ACCUMULATION

Irradiation induces the production of superoxide radicals (O O-2)((radical) (anion)), which play an important causative role in radiation damage. Manganese superoxide dismutase (MnSOD) is a mitochondrial enzyme involved in scavenging O-2((radical) (anion)). 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 E(2) 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 E(2) production. Our data indicate that the increase in MnSOD mRNA observed after irradiation occurs through both transcriptional and post-transcriptional mechanisms.