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.
Highlights
Ionizing radiation (IR) is commonly used to treat a wide variety of cancers
Exposure to IR leads to increased oxidative stress, DNAdamage, genomic instability and an increased inflammatory response; the transcription factor CCAAT enhancer binding protein delta (C/EBPd) is implicated in regulation of these same processes [21,22,23,24,25,27], but its role in radiation response has not been investigated
Exposure to IR leads to increased oxidative stress, DNA damage, genomic instability and inflammation [2]
Summary
Ionizing radiation (IR) is commonly used to treat a wide variety of cancers. Despite improvements in radiation technology, the delivery of radiotherapy to a tumor unavoidably affects the normal tissues surrounding it. Normal tissue toxicity often is a doselimiting factor, as the therapeutic ratio of radiotherapy is dictated by a balance between normal tissue toxicity and tumor control [1,2]. Normal tissue injury is a major side-effect of exposure to whole-body radiation, either in a clinical setting or during a nuclear accident. Normal tissue radiation toxicity mainly affects rapidly renewing cell systems, such as bone marrow and gastrointestinal (GI)-tract mucosa. There is a need for more effective agents to counteract IR-induced normal tissue injury [1,2]
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