Abstract
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.
Highlights
From the Division of Radiation Health, National Institute of Radiological Sciences, Chiba, Japan, 263 and the §Division of Hematology I Oncology, UCLA School of Medicine, Los Angeles, California 90024
These results suggest that induction of the Manganese superoxide dismutase (MnSOD) gene after irradiation is regulated, at least in part, by IL-l production and that increased levels of MnSOD transcripts occur through a pathway of endogenous prostaglandin E2 production
Previous studies have shown that cytokines such as granulocyte-macrophage colony-stimulating factor, tumor necrosis factor (TNF),1 and interleukin-1 (IL-l) are produced after irradiation in various cells [7,8,9,10,11,12,13]
Summary
(Received for publication, January 18, 1995, and in revised form, April 3, 1995). Makoto Akashi:j:, Misao Hachiya, Ronald L. Irradiation induces the production of superoxide radicals (02), which play an important causative role in radiation damage. 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-l production and that increased levels of MnSOD transcripts occur through a pathway of endogenous prostaglandin E2 production. In the presence of oxygen, irradiation or some chemicals increase the formation of superoxide radicals (02) [1, 2], which are important mediators of tissue damages [3, 4]. We explored the mechanisms for regulation of the MnSOD gene by irradiation
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