C/EBPδ deficiency sensitizes mice to ionizing radiation-induced hematopoietic and intestinal injury

• Published in: PloS one 2014-04, Vol.9 (4), p.e94967
• Main Authors: Pawar, Snehalata A, Shao, Lijian, Chang, Jianhui, Wang, Wenze, Pathak, Rupak, Zhu, Xiaoyan, Wang, Junru, Hendrickson, Howard, Boerma, Marjan, Sterneck, Esta, Zhou, Daohong, Hauer-Jensen, Martin
• Format: Article
• Language: English
• Subjects: Animal tissues; Animals; Apoptosis; Apoptosis - radiation effects; Biology and Life Sciences; Blood cells; Blood Cells - cytology; Blood Cells - radiation effects; Bone marrow; Bone Marrow Cells - cytology; Cancer; CCAAT-Enhancer-Binding Protein-delta - deficiency; CCAAT-Enhancer-Binding Protein-delta - metabolism; CCAAT/enhancer-binding protein; Cells (biology); Citrulline; Citrulline - blood; Crypts; Deoxyribonucleic acid; DNA; DNA Damage; Exposure; Gene Expression Regulation - radiation effects; Genes; Genomic instability; Hematopoietic Stem Cells - cytology; Hematopoietic Stem Cells - radiation effects; Histones - metabolism; Immunology; Injuries; Intestine; Intestines - cytology; Intestines - injuries; Intestines - radiation effects; Ionizing radiation; Irradiation; Laboratory animals; Lethality; Leukocytes; Leukocytes (mononuclear); Leukocytes (neutrophilic); Leukocytes, Mononuclear - cytology; Leukocytes, Mononuclear - radiation effects; Medical research; Medicine and Health Sciences; Mice; Mitosis - radiation effects; Myeloid cells; Myeloid Cells - cytology; Myeloid Cells - radiation effects; Nuclear accidents & safety; Osteoprogenitor cells; Oxidative stress; Pharmaceutical sciences; Platelets; Post-irradiation; Proteins; Radiation; Radiation damage; Radiation effects; Radiation injuries; Radiation Injuries - blood; Radiation Injuries - metabolism; Radiation Injuries - pathology; Radiation therapy; Radiation Tolerance; Research and Analysis Methods; Rodents; Stability; Stem cell transplantation; Stem cells; Stromal cells; Transcription factors; Whole-Body Irradiation - adverse effects
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0094967

Knowledge of the mechanisms involved in the radiation response is critical for developing interventions to mitigate radiation-induced injury to normal tissues. Exposure to radiation leads to increased oxidative stress, DNA-damage, genomic instability and inflammation. The transcription factor CCAAT/enhancer binding protein delta (Cebpd; C/EBPδ is implicated in regulation of these same processes, but its role in radiation response is not known. We investigated the role of C/EBPδ in radiation-induced hematopoietic and intestinal injury using a Cebpd knockout mouse model. Cebpd-/- mice showed increased lethality at 7.4 and 8.5 Gy total-body irradiation (TBI), compared to Cebpd+/+ mice. Two weeks after a 6 Gy dose of TBI, Cebpd-/- mice showed decreased recovery of white blood cells, neutrophils, platelets, myeloid cells and bone marrow mononuclear cells, decreased colony-forming ability of bone marrow progenitor cells, and increased apoptosis of hematopoietic progenitor and stem cells compared to Cebpd+/+ controls. Cebpd-/- mice exhibited a significant dose-dependent decrease in intestinal crypt survival and in plasma citrulline levels compared to Cebpd+/+ mice after exposure to radiation. This was accompanied by significantly decreased expression of γ-H2AX in Cebpd-/- intestinal crypts and villi at 1 h post-TBI, increased mitotic index at 24 h post-TBI, and increase in apoptosis in intestinal crypts and stromal cells of Cebpd-/- compared to Cebpd+/+ mice at 4 h post-irradiation. This study uncovers a novel biological function for C/EBPδ in promoting the response to radiation-induced DNA-damage and in protecting hematopoietic and intestinal tissues from radiation-induced injury.