title: A manganese superoxide dismutase (SOD2)-mediated adaptive response.
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.
authors.affiliation: Department of Radiation and Cellular Oncology, The University of Chicago, Chicago, IL 60637, USA. dgrdina@uchicago.edu
authors.forename: David J
authors.initials: DJ
authors.lastname: Grdina
authors.forename: Jeffrey S
authors.initials: JS
authors.lastname: Murley
authors.forename: Richard C
authors.initials: RC
authors.lastname: Miller
authors.forename: Helena J
authors.initials: HJ
authors.lastname: Mauceri
authors.forename: Harold G
authors.initials: HG
authors.lastname: Sutton
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Thirman
authors.forename: Jian Jian
authors.initials: JJ
authors.lastname: Li
authors.forename: Gayle E
authors.initials: GE
authors.lastname: Woloschak
authors.forename: Ralph R
authors.initials: RR
authors.lastname: Weichselbaum
mesh_terms: D000222:Adaptation, Physiological / Q000187:drug effects* / Q000528:radiation effects*; D000477:Alkylating Agents / Q000494:pharmacology; D000818:Animals; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects / Q000528:radiation effects; D004307:Dose-Response Relationship, Radiation; D005038:Ethylnitrosourea / Q000494:pharmacology; D005260:Female; D042822:Genomic Instability / Q000187:drug effects / Q000528:radiation effects; D006801:Humans; D008624:Mercaptoethylamines / Q000494:pharmacology; D051379:Mice; D008810:Mice, Inbred C57BL; D011247:Pregnancy; D015398:Signal Transduction / Q000187:drug effects / Q000528:radiation effects; D013482:Superoxide Dismutase / Q000378:metabolism*; D000099156:Superoxide Dismutase 2
chemical_list: D000477:Alkylating Agents; D005038:Ethylnitrosourea; D008624:Mercaptoethylamines; D013482:Superoxide Dismutase; D000099156:Superoxide Dismutase 2; C020174:N-(2-mercaptoethyl)-1,3-diaminopropane