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5-Androstenediol Promotes Survival of -Irradiated Human Hematopoietic Progenitors through Induction of Nuclear Factor-B Activation and Granulocyte Colony-Stimulating Factor Expression

Radiation Countermeasures Program, Armed Forces Radiobiology Research Institute, Uniformed Services University of the Health Sciences, Bethesda, Maryland

5-Androstenediol (5-AED) stimulates hematopoiesis and enhances survival in animals exposed to ionizing radiation (IR), suggesting that this steroid may act on hematopoietic progenitor cells. We used -irradiated primary human CD34⁺ hematopoietic progenitor cells to show that 5-AED protects hematopoietic cells from IR damage, as shown by enhanced cell survival, clonogenicity, proliferation, and differentiation. Unlike in tumor cells, IR did not induce nuclear factor-B (NFB) activation in primary progenitors. However, IR stimulated IB_β release from NFB/IB complexes and caused NFB1 (p50) degradation. 5-AED stabilized NFB1 in irradiated cells and induced NFB gene expression and NFB activation (DNA binding). 5-AED stimulated interleukin-6 and granulocyte colony-stimulating factor (G-CSF) secretion. The survival-enhancing effects of 5-AED on clonogenic cells were abrogated by small interfering RNA inhibition of NFB gene expression and by neutralization of G-CSF with antibody. The effects of 5-AED on survival and G-CSF secretion were blocked by the NFB inhibitor N-benzoyloxycarbonyl (Z)-Leu-Leu-leucinal (MG132). 5-AED had no effect on accumulation of the proapoptotic factor p53 after IR, as determined by Western blot. The results indicate that NFB1 degradation after IR may be responsible for the radiation sensitivity of CD34⁺ cells compared with tumor cells. 5-AED exerts survival-enhancing effects on irradiated human hematopoietic progenitor cells via induction, stabilization, and activation of NFB, which results in increased secretion of hematopoietic growth factor G-CSF.

Address correspondence to: Dr. Mang Xiao, Armed Forces Radiobiology Research Institute, 8901 Wisconsin Ave., Bethesda, MD 20889-5603. E-mail: xiao{at}afrri.usuhs.mil