title: C/EBPδ deficiency sensitizes mice to ionizing radiation-induced hematopoietic and intestinal injury.
abstract: 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.
authors.affiliation: Division of Radiation Health, Department of Pharmaceutical Sciences, University of Arkansas for Medical Sciences, Little Rock, Arkansas, United States of America.
authors.forename: Snehalata A
authors.initials: SA
authors.lastname: Pawar
authors.affiliation: Division of Radiation Health, Department of Pharmaceutical Sciences, University of Arkansas for Medical Sciences, Little Rock, Arkansas, United States of America.
authors.forename: Lijian
authors.initials: L
authors.lastname: Shao
authors.affiliation: Division of Radiation Health, Department of Pharmaceutical Sciences, University of Arkansas for Medical Sciences, Little Rock, Arkansas, United States of America.
authors.forename: Jianhui
authors.initials: J
authors.lastname: Chang
authors.affiliation: Division of Radiation Health, Department of Pharmaceutical Sciences, University of Arkansas for Medical Sciences, Little Rock, Arkansas, United States of America.
authors.forename: Wenze
authors.initials: W
authors.lastname: Wang
authors.affiliation: Division of Radiation Health, Department of Pharmaceutical Sciences, University of Arkansas for Medical Sciences, Little Rock, Arkansas, United States of America.
authors.forename: Rupak
authors.initials: R
authors.lastname: Pathak
authors.affiliation: Division of Radiation Health, Department of Pharmaceutical Sciences, University of Arkansas for Medical Sciences, Little Rock, Arkansas, United States of America.
authors.forename: Xiaoyan
authors.initials: X
authors.lastname: Zhu
authors.affiliation: Division of Radiation Health, Department of Pharmaceutical Sciences, University of Arkansas for Medical Sciences, Little Rock, Arkansas, United States of America.
authors.forename: Junru
authors.initials: J
authors.lastname: Wang
authors.affiliation: Department of Pharmaceutical Sciences, University of Arkansas for Medical Sciences, Little Rock, Arkansas, United States of America.
authors.forename: Howard
authors.initials: H
authors.lastname: Hendrickson
authors.affiliation: Division of Radiation Health, Department of Pharmaceutical Sciences, University of Arkansas for Medical Sciences, Little Rock, Arkansas, United States of America.
authors.forename: Marjan
authors.initials: M
authors.lastname: Boerma
authors.affiliation: Center for Cancer Research, National Cancer Institute, Frederick, Maryland, United States of America.
authors.forename: Esta
authors.initials: E
authors.lastname: Sterneck
authors.affiliation: Division of Radiation Health, Department of Pharmaceutical Sciences, University of Arkansas for Medical Sciences, Little Rock, Arkansas, United States of America.
authors.forename: Daohong
authors.initials: D
authors.lastname: Zhou
authors.affiliation: Division of Radiation Health, Department of Pharmaceutical Sciences, University of Arkansas for Medical Sciences, Little Rock, Arkansas, United States of America; Surgical Service, Central Arkansas Veterans Healthcare System, Little Rock, Arkansas, United States of America.
authors.forename: Martin
authors.initials: M
authors.lastname: Hauer-Jensen
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000528:radiation effects; D001773:Blood Cells / Q000166:cytology / Q000528:radiation effects; D001854:Bone Marrow Cells / Q000166:cytology; D051743:CCAAT-Enhancer-Binding Protein-delta / Q000172:deficiency* / Q000378:metabolism; D002956:Citrulline / Q000097:blood; D004249:DNA Damage; D005786:Gene Expression Regulation / Q000528:radiation effects; D006412:Hematopoietic Stem Cells / Q000166:cytology / Q000528:radiation effects*; D006657:Histones / Q000378:metabolism; D007422:Intestines / Q000166:cytology / Q000293:injuries* / Q000528:radiation effects*; D007963:Leukocytes, Mononuclear / Q000166:cytology / Q000528:radiation effects; D051379:Mice; D008938:Mitosis / Q000528:radiation effects; D022423:Myeloid Cells / Q000166:cytology / Q000528:radiation effects; D011832:Radiation Injuries / Q000097:blood / Q000378:metabolism* / Q000473:pathology; D011836:Radiation Tolerance; D014916:Whole-Body Irradiation / Q000009:adverse effects
chemical_list: D006657:Histones; C475961:gamma-H2AX protein, mouse; D051743:CCAAT-Enhancer-Binding Protein-delta; D002956:Citrulline
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