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Impact of inflammatory signaling on radiation biodosimetry: mouse model of inflammatory bowel disease.

ABSTRACT: BACKGROUND:Ionizing Radiation (IR) is a known pro-inflammatory agent and in the process of development of biomarkers for radiation biodosimetry, a chronic inflammatory disease condition could act as a confounding factor. Hence, it is important to develop radiation signatures that can distinguish between IR-induced inflammatory responses and pre-existing disease. In this study, we compared the gene expression response of a genetically modified mouse model of inflammatory bowel disease (Il10-/-) with that of a normal wild-type mouse to potentially develop transcriptomics-based biodosimetry markers that can predict radiation exposure in individuals regardless of pre-existing inflammatory condition. RESULTS:Wild-type (WT) and Il10-/- mice were exposed to whole body irradiation of 7?Gy X-rays. Gene expression responses were studied using high throughput whole genome microarrays in peripheral blood 24?h post-irradiation. Analysis resulted in identification of 1962 and 1844 genes differentially expressed (p

SUBMITTER: Mukherjee S

PROVIDER: S-EPMC6498469 | biostudies-literature | 2019 May

REPOSITORIES: biostudies-literature

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Impact of inflammatory signaling on radiation biodosimetry: mouse model of inflammatory bowel disease.

Mukherjee Sanjay S Laiakis Evagelia C EC Fornace Albert J AJ Amundson Sally A SA

BMC genomics 20190502 1

<h4>Background</h4>Ionizing Radiation (IR) is a known pro-inflammatory agent and in the process of development of biomarkers for radiation biodosimetry, a chronic inflammatory disease condition could act as a confounding factor. Hence, it is important to develop radiation signatures that can distinguish between IR-induced inflammatory responses and pre-existing disease. In this study, we compared the gene expression response of a genetically modified mouse model of inflammatory bowel disease (Il ...[more]

PMID: 31046668

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Project description:Background: Ionizing Radiation (IR) is a known pro-inflammatory agent and in the process of development of biomarkers for radiation biodosimetry a chronic inflammatory disease condition could act as a confounding factor. Hence, it is important to develop radiation biodosimetry that can distinguish between IR-induced inflammatory responses and pre-existing disease. In this study, we compared the gene expression response of a genetically modified mouse model of inflammatory bowel disease (Il10-/-) with that of a normal wild-type mouse to potentially develop transcriptomic based biodosimetry markers for individual susceptibility to radiation. Results: Wild-type (WT) and Il10-/- mice were exposed to whole body irradiation of 7Gy (LD50/30 for IL10-/-) X-rays. Gene expression responses were studied using high throughput whole genome microarrays in peripheral blood after 24h post-irradiation. Analysis resulted in identification of 1962 and 1844 genes differentially expressed (p < 0.001, FDR < 10%) after radiation exposure in Il10-/- and WT mice respectively. A set of 155 genes were also identified as differentially expressing between WT and Il10-/- mice at the baseline pre-irradiation level. Gene ontology analysis revealed that the baseline differentially expressing genes (155) were mainly involved in Inflammatory response, Glutathione metabolism and fibrosis. Analysis of radiation responsive genes revealed commonality of immune function genes between WT and Il10-/- mice. Gene ontology analysis revealed that innate immune response and p53 signaling processes were strongly associated with up-regulated genes whereas, B-cell development process was found to be significant amongst downregulated genes in response to radiation in the two genotypes. However, specific immune response pathways like MHC class I antigen presentation and response to viral/bacterial infection were particularly associated with radiation responsive genes of Il10-/- mice but not with WT mice. Further analysis of activation status of specific canonical pathways and upstream regulators using IPA-prediction tool revealed significant difference in the activation status of T-cell and hormone mediated signaling as well as regulators of inflammation between WT and Il10-/- after irradiation.

Project description:Inflammatory bowel disease (IBD) is one of the immune-related gastrointestinal disorders, including ulcerative colitis and Crohn's disease, that affects the life quality of millions of people worldwide. IBD symptoms include abdominal pain, diarrhea, and rectal bleeding, which may result from the interactions among gut microbiota, food components, intestinal epithelial cells, and immune cells. It is of particular importance to assess how each key gene expressed in intestinal epithelial and immune cells affects inflammation in the colon. G protein-coupled taste receptors, including G protein subunit α-gustducin and other signaling proteins, have been found in the intestines. Here, we use α-gustducin as a representative and describe a dextran sulfate sodium (DSS)-induced IBD model to evaluate the effect of gustatory gene mutations on gut mucosal immunity and inflammation. This method combines gene knockout technology with the chemically induced IBD model, and thus can be applied to assess the outcome of gustatory gene nullification as well as other genes that may exuberate or dampen the DSS-induced immune response in the colon. Mutant mice are administered with DSS for a certain period during which their body weight, stool, and rectal bleeding are monitored and recorded. At different timepoints during administration, some mice are euthanized, then the sizes and weights of their spleens and colons are measured and gut tissues are collected and processed for histological and gene expression analyses. The data show that the α-gustducin knockout results in excessive weight loss, diarrhea, intestinal bleeding, tissue damage, and inflammation vs. wild-type mice. Since the severity of induced inflammation is affected by mouse strains, housing environment, and diet, optimization of DSS concentration and administration duration in a pilot experiment is particularly important. By adjusting these factors, this method can be applied to assess both anti- and pro-inflammatory effects.

Dataset Information

Impact of inflammatory signaling on radiation biodosimetry: mouse model of inflammatory bowel disease.

Publications

Impact of inflammatory signaling on radiation biodosimetry: mouse model of inflammatory bowel disease.

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