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18 November 2015 Role of Pro-inflammatory Cytokines in Radiation-Induced Genomic Instability in Human Bronchial Epithelial Cells
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Abstract
Inflammatory cytokines have been implicated in the regulation of radiation-induced genomic instability in the hematopoietic system and have also been shown to induce chronic DNA damage responses in radiation-induced senescence. We have previously shown that human bronchial epithelial cells (HBEC3-KT) have increased genomic instability and IL-8 production persisting at day 7 after exposure to high-LET (600 MeV/nucleon 56Fe ions) compared to low-LET (320 keV X rays) radiation. Thus, we investigated whether IL-8 induction is part of a broader pro-inflammatory response produced by the epithelial cells in response to damage, which influences genomic instability measured by increased micronuclei and DNA repair foci frequencies. We found that exposure to radiation induced the release of multiple inflammatory cytokines into the media, including GM-CSF, GROα, IL-1α, IL-8 and the inflammation modulator, IL-1 receptor antagonist (IL-1RA). Our results suggest that this is an IL-1α-driven response, because an identical signature was induced by the addition of recombinant IL-1α to nonirradiated cells and functional interference with recombinant IL-1RA (Anakinra) or anti-IL-1α function-blocking antibody, decreased IL-8 production induced by radiation exposure. However, genomic instability was not influenced by this pathway as addition of recombinant IL-1α to naive or irradiated cells or the presence of IL-1 RA under the same conditions as those that interfered with the function of IL-8, did not affect micronuclei or DNA repair foci frequencies measured at day 7 after exposure. While dose-response studies revealed that genomic instability and IL-8 production are the consequences of targeted effects, experiments employing a co-culture transwell system revealed the propagation of pro-inflammatory responses but not genomic instability from irradiated to nonirradiated cells. Collectively, these results point to a cell-autonomous mechanism sustaining radiation-induced genomic instability in this model system and suggest that while molecules associated with these mechanisms could be markers for persisting damage, they reflect two different outcomes.
Erica Werner, Huichen Wang and Paul W. Doetsch "Role of Pro-inflammatory Cytokines in Radiation-Induced Genomic Instability in Human Bronchial Epithelial Cells," Radiation Research 184(6), (18 November 2015). https://doi.org/10.1667/RR14045.1
Received: 5 February 2015; Accepted: 1 September 2015; Published: 18 November 2015
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