A manganese superoxide dismutase (SOD2)-mediated adaptive response

David J. Grdina, Jeffrey S. Murley, Richard C. Miller, Helena J. Mauceri, Harold G. Sutton, Michael J. Thirman, Jian-Jian Li, Gayle E. Woloschak, Ralph R. Weichselbaum

Research output: Contribution to journalArticle

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Abstract

Very low doses of ionizing radiation, 5 to 100 mGy, can induce adaptive responses characterized by elevation in cell survival and reduction in micronuclei formation. Utilizing these end points, RKO human colon carcinoma and transformed mouse embryo fibroblasts (MEF), wild-type or knockout cells missing TNF receptors 1 and 2 (TNFR1-R2-), and C57BL/6 and TNFR1-R2- knockout mice, we demonstrate that intact TNF signaling is required for induction of elevated manganese superoxide dismutase (SOD2) activity (P < 0.001) and the subsequent expression of these SOD2-mediated adaptive responses when cells are challenged at a later time with 2 Gy. In contrast, amifostine's free thiol form WR1065 can directly activate NF-κB giving rise to elevated SOD2 activity 24 h later and induce an adaptive response in both MEF wild-type and TNF signaling defective TNFR1 -R2- cells. Transfection of cells with SOD2 siRNA completely abolishes both the elevation in SOD2 activity and expression of the adaptive responses. These results were confirmed in vivo using a micronucleus assay in splenocytes derived from C57BL/6 and TNFR1-R2- knockout mice that were exposed to 100 mGy or 400 mg/kg amifostine 24 h prior to exposure to a 2 Gy whole-body dose. A dose of 100 mGy also conferred enhanced protection to C57BL/6 mice exposed 24 h later to 100 mg/kg of N-Ethyl-N-nitrosourea (ENU). While very low radiation doses require an intact TNF signaling process to induce a SOD2-mediated adaptive response, amifostine can induce a similar adaptive response in both TNF receptor competent and knockout cells, respectively.

Original languageEnglish (US)
Pages (from-to)115-124
Number of pages10
JournalRadiation Research
Volume179
Issue number2
DOIs
StatePublished - Feb 2013

Fingerprint

inorganic peroxides
Receptors, Tumor Necrosis Factor, Type I
Superoxide Dismutase
manganese
Amifostine
knockout mice
Tumor Necrosis Factor Receptors
mice
dosage
cells
Knockout Mice
embryos
fibroblasts
Embryonic Structures
Fibroblasts
Ethylnitrosourea
Micronucleus Tests
Ionizing Radiation
Inbred C57BL Mouse
Sulfhydryl Compounds

ASJC Scopus subject areas

  • Radiology Nuclear Medicine and imaging
  • Biophysics
  • Radiation

Cite this

Grdina, D. J., Murley, J. S., Miller, R. C., Mauceri, H. J., Sutton, H. G., Thirman, M. J., ... Weichselbaum, R. R. (2013). A manganese superoxide dismutase (SOD2)-mediated adaptive response. Radiation Research, 179(2), 115-124. https://doi.org/10.1667/RR3126.2

A manganese superoxide dismutase (SOD2)-mediated adaptive response. / Grdina, David J.; Murley, Jeffrey S.; Miller, Richard C.; Mauceri, Helena J.; Sutton, Harold G.; Thirman, Michael J.; Li, Jian-Jian; Woloschak, Gayle E.; Weichselbaum, Ralph R.

In: Radiation Research, Vol. 179, No. 2, 02.2013, p. 115-124.

Research output: Contribution to journalArticle

Grdina, DJ, Murley, JS, Miller, RC, Mauceri, HJ, Sutton, HG, Thirman, MJ, Li, J-J, Woloschak, GE & Weichselbaum, RR 2013, 'A manganese superoxide dismutase (SOD2)-mediated adaptive response', Radiation Research, vol. 179, no. 2, pp. 115-124. https://doi.org/10.1667/RR3126.2
Grdina DJ, Murley JS, Miller RC, Mauceri HJ, Sutton HG, Thirman MJ et al. A manganese superoxide dismutase (SOD2)-mediated adaptive response. Radiation Research. 2013 Feb;179(2):115-124. https://doi.org/10.1667/RR3126.2
Grdina, David J. ; Murley, Jeffrey S. ; Miller, Richard C. ; Mauceri, Helena J. ; Sutton, Harold G. ; Thirman, Michael J. ; Li, Jian-Jian ; Woloschak, Gayle E. ; Weichselbaum, Ralph R. / A manganese superoxide dismutase (SOD2)-mediated adaptive response. In: Radiation Research. 2013 ; Vol. 179, No. 2. pp. 115-124.
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