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Linear Energy Transfer Modulates Radiation-Induced NF-kappa B Activation and Expression of its Downstream Target Genes

Chishti, Arif Ali and Baumstark-Khan, Christa and Koch, Kristina and Kolanus, Waldemar and Feles, Sebastian and Konda, Bikash and Azhar, Abid and Spitta, Luis F. and Henschenmacher, Bernd and Diegeler, Sebastian and Schmitz, Claudia and Hellweg, Christine Elisabeth (2018) Linear Energy Transfer Modulates Radiation-Induced NF-kappa B Activation and Expression of its Downstream Target Genes. Radiation Research, 189 (4), pp. 354-370. Radiation Research Society. DOI: 10.1667/RR14905.1 ISSN 0033-7587

Full text not available from this repository.

Official URL: http://dx.doi.org/10.1667/RR14905.1

Abstract

Nuclear factor kappaB (NF-κB) is a central transcription factor in the immune system and modulates cell survival in response to radiotherapy. Activation of NF-κB was shown to be an early step in the cellular response to ultraviolet A (UVA) and ionizing radiation exposure in human cells. NF-κB activation by the genotoxic stress-dependent sub-pathway after exposure to different radiation qualities had been evaluated to a very limited extent. In addition, the resulting gene expression profile, which shapes the cellular and tissue response, is unknown. Therefore, in this study the activation of NF-κB after exposure to low- and high-linear energy transfer (LET) radiation and the expression of its target genes were analyzed in human embryonic kidney (HEK) cells. The activation of NF-κB via canonical and genotoxic stress-induced pathways was visualized by the cell line HEK-pNF-κB-d2EGFP/Neo L2 carrying the destabilized enhanced green fluorescent protein (d2EGFP) as reporter. The NF-κB-dependent d2EGFP expression after irradiation with X rays and heavy ions was evaluated by flow cytometry. Because of differences in the extent of NF-κB activation after irradiation with X rays (significant NF-κB activation for doses >4 Gy) and heavy ions (significant NF-κB activation at doses as low as 1 Gy), it was expected that radiation quality (LET) played an important role in the cellular radiation response. In addition, the relative biological effectiveness (RBE) of NF-κB activation and reduction of cellular survival were compared for heavy ions having a broad LET range (∼0.3–9,674 keV/μm). Furthermore, the effect of LET on NF-κB target gene expression was analyzed by real-time reverse transcriptase quantitative PCR (RT-qPCR). The maximal RBE for NF-κB activation and cell killing occurred at an LET value of 80 and 175 keV/μm, respectively. There was a dose-dependent increase in expression of NF-κB target genes NF-κB1A and CXCL8. A qPCR array of 84 NF-κB target genes revealed that TNF and a set of CXCL genes (CXCL1, CXCL2, CXCL8, CXCL10), CCL2, VCAM1, CD83, NF-κB1, NF-κB2 and NF-κBIA were strongly upregulated after exposure to X rays and neon ions (LET 92 keV/μm). After heavy-ion irradiations, it was noted that the expression of NF-κB target genes such as chemokines and CD83 was highest at an LET value that coincided with the LET resulting in maximal NF-κB activation, whereas expression of the NF-κB inhibitory gene NFKBIA was induced transiently by all radiation qualities investigated. Taken together, these findings clearly demonstrate that NF-κB activation and NF-κB-dependent gene expression by heavy ions are highest in the LET range of ∼50–200 keV/μm. The upregulated chemokines and cytokines (CXCL1, CXCL2, CXCL10, CXCL8/IL-8 and TNF) could be important for cell–cell communication among hit as well as nonhit cells (bystander effect).

Item URL in elib:https://elib.dlr.de/119656/
Document Type:Article
Title:Linear Energy Transfer Modulates Radiation-Induced NF-kappa B Activation and Expression of its Downstream Target Genes
Authors:
AuthorsInstitution or Email of AuthorsAuthors ORCID iD
Chishti, Arif AliRadiation Biology Department, Institute of Aerospace Medicine, German Aerospace Center (DLR), Cologne, Germany.UNSPECIFIED
Baumstark-Khan, ChristaRadiation Biology Department, Institute of Aerospace Medicine, German Aerospace Center (DLR), Cologne, Germany.UNSPECIFIED
Koch, KristinaRadiation Biology Department, Institute of Aerospace Medicine, German Aerospace Center (DLR), Cologne, Germany.UNSPECIFIED
Kolanus, WaldemarLife and Medical Sciences (LIMES) Institute, University of Bonn, Bonn, GermanyUNSPECIFIED
Feles, SebastianRadiation Biology Department, Institute of Aerospace Medicine, German Aerospace Center (DLR), Cologne, Germany.UNSPECIFIED
Konda, BikashRadiation Biology Department, Institute of Aerospace Medicine, German Aerospace Center (DLR), Cologne, Germany.UNSPECIFIED
Azhar, AbidThe Karachi Institute of Biotechnology and Genetic Engineering, University of Karachi, Karachi-75270, PakistanUNSPECIFIED
Spitta, Luis F.Radiation Biology Department, Institute of Aerospace Medicine, German Aerospace Center (DLR), Cologne, Germany.UNSPECIFIED
Henschenmacher, BerndRadiation Biology Department, Institute of Aerospace Medicine, German Aerospace Center (DLR), Cologne, Germany.UNSPECIFIED
Diegeler, SebastianRadiation Biology Department, Institute of Aerospace Medicine, German Aerospace Center (DLR), Cologne, Germany.UNSPECIFIED
Schmitz, ClaudiaRadiation Biology Department, Institute of Aerospace Medicine, German Aerospace Center (DLR), Cologne, Germany.UNSPECIFIED
Hellweg, Christine ElisabethRadiation Biology Department, Institute of Aerospace Medicine, German Aerospace Center (DLR), Cologne, Germany; Christine.Hellweg (at) dlr.dehttps://orcid.org/0000-0002-2223-3580
Date:25 January 2018
Journal or Publication Title:Radiation Research
Refereed publication:Yes
Open Access:No
Gold Open Access:No
In SCOPUS:Yes
In ISI Web of Science:Yes
Volume:189
DOI :10.1667/RR14905.1
Page Range:pp. 354-370
Publisher:Radiation Research Society
ISSN:0033-7587
Status:Published
Keywords:Nuclear factor kappaB (NF-κB)
HGF - Research field:Aeronautics, Space and Transport
HGF - Program:Space
HGF - Program Themes:Research under Space Conditions
DLR - Research area:Raumfahrt
DLR - Program:R FR - Forschung unter Weltraumbedingungen
DLR - Research theme (Project):R - Vorhaben Strahlenbiologie
Location: Köln-Porz
Institutes and Institutions:Institute of Aerospace Medicine > Radiation Biology
Deposited By: Kopp, Kerstin
Deposited On:16 Apr 2018 09:56
Last Modified:06 Sep 2019 15:19

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