title: 5-AED enhances survival of irradiated mice in a G-CSF-dependent manner, stimulates innate immune cell function, reduces radiation-induced DNA damage and induces genes that modulate cell cycle progression and apoptosis.
abstract: The steroid androst-5-ene-3ß,17ß-diol (5-androstenediol, 5-AED) elevates circulating granulocytes and platelets in animals and humans, and enhances survival during the acute radiation syndrome (ARS) in mice and non-human primates. 5-AED promotes survival of irradiated human hematopoietic progenitors in vitro through induction of Nuclear Factor-κB (NFκB)-dependent Granulocyte Colony-Stimulating Factor (G-CSF) expression, and causes elevations of circulating G-CSF and interleukin-6 (IL-6). However, the in vivo cellular and molecular effects of 5-AED are not well understood. The aim of this study was to investigate the mechanisms of action of 5-AED administered subcutaneously (s.c.) to mice 24 h before total body γ- or X-irradiation (TBI). We used neutralizing antibodies, flow cytometric functional assays of circulating innate immune cells, analysis of expression of genes related to cell cycle progression, DNA repair and apoptosis, and assessment of DNA strand breaks with halo-comet assays. Neutralization experiments indicated endogenous G-CSF but not IL-6 was involved in survival enhancement by 5-AED. In keeping with known effects of G-CSF on the innate immune system, s.c. 5-AED stimulated phagocytosis in circulating granulocytes and oxidative burst in monocytes. 5-AED induced expression of both bax and bcl-2 in irradiated animals. Cdkn1a and ddb1, but not gadd45a expression, were upregulated by 5-AED in irradiated mice. S.c. 5-AED administration caused decreased DNA strand breaks in splenocytes from irradiated mice. Our results suggest 5-AED survival enhancement is G-CSF-dependent, and that it stimulates innate immune cell function and reduces radiation-induced DNA damage via induction of genes that modulate cell cycle progression and apoptosis.
authors: Radiation Countermeasures Program, Armed Forces Radiobiology Research Institute, Uniformed Services University of the Health Sciences, 8901 Wisconsin Ave, Bethesda, MD 20889-5603, USA.
authors: Marcy B
authors: MB
authors: Grace
authors: Vijay K
authors: VK
authors: Singh
authors: Juong G
authors: JG
authors: Rhee
authors: William E
authors: WE
authors: Jackson
authors: Tzu-Cheg
authors: TC
authors: Kao
authors: Mark H
authors: MH
authors: Whitnall
mesh_terms: D054508:Acute Radiation Syndrome / Q000473:pathology / Q000503:physiopathology* / Q000517:prevention & control*; D015114:Androstenediol / Q000008:administration & dosage*; D000818:Animals; D051017:Apoptosis Regulatory Proteins / Q000378:metabolism*; D018797:Cell Cycle Proteins / Q000378:metabolism*; D004249:DNA Damage / Q000187:drug effects* / Q000235:genetics; D016179:Granulocyte Colony-Stimulating Factor / Q000378:metabolism; D007113:Immunity, Innate / Q000187:drug effects / Q000276:immunology*; D008297:Male; D051379:Mice; D011837:Radiation-Protective Agents / Q000008:administration & dosage; D015996:Survival Rate; D015854:Up-Regulation / Q000187:drug effects
chemical_list: D051017:Apoptosis Regulatory Proteins; D018797:Cell Cycle Proteins; D011837:Radiation-Protective Agents; D016179:Granulocyte Colony-Stimulating Factor; D015114:Androstenediol