A role for manganese superoxide dismutase in radioprotection of hematopoietic stem cells by interleukin-1

Abstract

Pretreatment with interleukin-1 (IL-1) has been shown to protect mice from the myelotoxicity associated with irradiation via a mechanism potentially mediated through the induction of the antioxidant enzyme manganese superoxide dismutase (MnSOD). In this study, we have compared the ability of IL-1 to induce MnSOD mRNA in murine bone marrow cells and human cell lines with its ability to protect these cells against the damaging effects of ionizing radiation. Bone marrow cells obtained from mice 6 hours after a single injection of IL-1 demonstrate a dose- dependent increase in the expression of MnSOD RNA. In this same study, IL-1 was also shown to be radioprotective when given to mice 20 hours before lethal irradiation. Similarly, in vitro treatment with IL-1 of bone marrow cells isolated from 5-fluorouracil-treated mice results in elevated levels of MnSOD RNA. Pretreatment with IL-1 also protected bone marrow long-term culture-initiating cells capable of reconstituting irradiated stromal cultures from an irradiation insult. Furthermore, IL-1-treated human bone marrow cells display both elevated MnSOD RNA and protein levels when compared with media controls. The human A375 melanoma, A549 adenocarcinoma, and factor-dependent TF-1 leukemic cell lines demonstrate low basal MnSOD RNA levels that increase following treatment with IL-1. For the A375 cells, this correlates with increased MnSOD protein expression and radioprotection by IL-1 using a colony assay. In contrast, the chronic myelogenous leukemic cell line, K562, displays a high basal MnSOD RNA level, and this RNA expression is not further increased by IL-1 treatment. In addition, these cells are comparatively radioresistant and are not further protected by IL-1 treatment. Finally, the Mo-7 cell line displays a low basal level of MnSOD RNA that correlates with a high sensitivity to irradiation and IL-1 pretreatment has no effect on MnSOD RNA levels. Our results indicate that increased radioprotection by IL-1 correlates with the induction of the antioxidant enzyme MnSOD and this induction may be an important factor in IL-1 radioprotection.

Radioprotection and Radiomitigation: From the Bench to Clinical Practice

“…Preliminary research showed that a bovine SOD IV injection to mice promoted erythrocyte, reticulocyte, and white blood cell recovery after an X irradiation-induced loss [97]. This observation is in agreement with later experiments that correlated the radioprotection in hematopoietic stem cells with the IL-1-induced increase in SOD2 activity [98]. As reported by Yan et al [99], when a single dose of 35 Gy was injected to mice, the SC injection of AAV2-Mn-SOD-hrGFP (a recombinant adeno-associated virus vector expressing SOD2 tagged with humanized recombinant green fluorescent protein) showed significant mitigation and enhanced the speed of healing process, in 2 weeks after radiation in comparison with the control group.…”