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.
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1 December 2015
REGULAR ARTICLES|
November 18 2015
Role of Pro-inflammatory Cytokines in Radiation-Induced Genomic Instability in Human Bronchial Epithelial Cells
Erica Werner;
Erica Werner
1
a Department of Biochemistry, Emory University School of Medicine, Atlanta, Georgia;
1 Address for correspondence: 1510 Clifton Rd., Rm 4013, Rollins O. Wayne Research Center, Emory University School of Medicine, Atlanta, GA 30322; emails: [email protected] and [email protected].
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Huichen Wang;
Huichen Wang
b Department of Physics, Radiation Institute for Science and Engineering (RaISE), Prairie View A&M University, Prairie View, Texas; and
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Paul W. Doetsch
Paul W. Doetsch
1
a Department of Biochemistry, Emory University School of Medicine, Atlanta, Georgia;
c Departments of Radiation Oncology and Department of Hematology and Medical Oncology, Winship Cancer Institute, Emory University School of Medicine, Atlanta, Georgia
1 Address for correspondence: 1510 Clifton Rd., Rm 4013, Rollins O. Wayne Research Center, Emory University School of Medicine, Atlanta, GA 30322; emails: [email protected] and [email protected].
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Radiat Res (2015) 184 (6): 621–629.
Article history
Received:
February 05 2015
Accepted:
September 09 2015
Citation
Erica Werner, Huichen Wang, Paul W. Doetsch; Role of Pro-inflammatory Cytokines in Radiation-Induced Genomic Instability in Human Bronchial Epithelial Cells. Radiat Res 1 December 2015; 184 (6): 621–629. doi: https://doi.org/10.1667/RR14045.1
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