Genetic Analysis of Susceptibility to Dextran Sulfate Sodium-Induced Colitis in Mice

Mähler, Michael; Bristol, Ian J.; Sundberg, John P.; Churchill, Gary A.; Birkenmeier, Edward H.; Elson, Charles O.; Leiter, Edward H.

doi:10.1006/geno.1998.5636

Cited by 93 publications

(57 citation statements)

References 51 publications

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“…The effect of genotype was observed in two different strain backgrounds: inbred 129svev (Figures 3 and 4) and a fifth generation backcross into a C57BL/6 background (data not shown). The latter is important, given the role of strain background in susceptibility to DSS colitis (44,45).…”

Section: Resultsmentioning

confidence: 99%

Increased sensitivity to dextran sodium sulfate colitis in IRE1β-deficient mice

Bertolotti¹,

Wang²,

Novoa³

et al. 2001

J. Clin. Invest.

379

352

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The epithelial cells of the gastrointestinal tract are exposed to toxins and infectious agents that can adversely affect protein folding in the endoplasmic reticulum (ER) and cause ER stress. The IRE1 genes are implicated in sensing and responding to ER stress signals. We found that epithelial cells of the gastrointestinal tract express IRE1β, a specific isoform of IRE1. BiP protein, a marker of ER stress, was elevated in the colonic mucosa of IRE1β -/-mice, and, when exposed to dextran sodium sulfate (DSS) to induce inflammatory bowel disease, mutant mice developed colitis 3-5 days earlier than did wild-type or IRE1β +/-mice. The inflammation marker ICAM-1 was also expressed earlier in the colonic mucosa of DSS-treated IRE1β -/-mice, indicating that the mutation had its impact early in the inflammatory process, before the onset of mucosal ulceration. These findings are consistent with a model whereby perturbations in ER function, which are normally mitigated by the activity of IRE1β, participate in the development of colitis.

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Section: Resultsmentioning

confidence: 99%

Increased sensitivity to dextran sodium sulfate colitis in IRE1β-deficient mice

Bertolotti¹,

Wang²,

Novoa³

et al. 2001

J. Clin. Invest.

379

352

View full text Add to dashboard Cite

show abstract

“…Previous studies have found QTL in this region for metabolismrelated phenotypes, including blood glucose level (47), plasma levels of sterol (48), and growth and body fat parameters (49,50). In addition, QTL for immunerelated phenotypes, including natural killer T cell number in the thymus (51), experimentally induced induced colitis (52), and chemically induced bladder tumorigenesis (53), also map to this locus. It will be interesting to see whether the genes with trans-eQTL at this locus may be related to those phenotypes.…”

Section: Original Researchmentioning

confidence: 99%

Integrative Genetic Analysis of Allergic Inflammation in the Murine Lung

Kelada

Carpenter

Aylor

et al. 2014

Am J Respir Cell Mol Biol

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Airway allergen exposure induces inflammation among individuals with atopy that is characterized by altered airway gene expression, elevated levels of T helper type 2 cytokines, mucus hypersecretion, and airflow obstruction. To identify the genetic determinants of the airway allergen response, we employed a systems genetics approach. We applied a house dust mite mouse model of allergic airway disease to 151 incipient lines of the Collaborative Cross, a new mouse genetic reference population, and measured serum IgE, airway eosinophilia, and gene expression in the lung. Allergen-induced serum IgE and airway eosinophilia were not correlated. We detected quantitative trait loci (QTL) for airway eosinophilia on chromosome (Chr) 11 (71.802-87.098 megabases [Mb]) and allergen-induced IgE on Chr 4 (13.950-31.660 Mb). More than 4,500 genes expressed in the lung had gene expression QTL (eQTL), the majority of which were located near the gene itself. However, we also detected approximately 1,700 trans-eQTL, and many of these trans-eQTL clustered into two regions on Chr 2. We show that one of these loci (at 147.6 Mb) is associated with the expression of more than 100 genes, and, using bioinformatics resources, fine-map this locus to a 53 kb-long interval. We also use the gene expression and eQTL data to identify a candidate gene, Tlcd2, for the eosinophil QTL. Our results demonstrate that hallmark allergic airway disease phenotypes are associated with distinct genetic loci on Chrs 4 and 11, and that gene expression in the allergically inflamed lung is controlled by both cis and trans regulatory factors.

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“…Colitis was induced in gp91 phoxÀ/À and WT mice by administering ad libitum 2.5% w/v DSS, molecular weight 36 000-44 000; (ICN Biomedicals Australasia, Sydney, Australia) dissolved in drinking water for 7 consecutive days, as described, [12][13][14]29 whereas control groups received normal tap water. It has been reported recently that DSS-induced colitis resulted from influx of bacteria into the lamina propria, due to an alteration of the colonic inner mucus layer.…”

Section: Dss Treatmentmentioning

confidence: 99%

Gp91^phox contributes to the development of experimental inflammatory bowel disease

Bao

Carr

et al. 2011

Immunol Cell Biol

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Inflammatory bowel disease (IBD) is related to dysfunction of intestinal immunity. Neutrophils have an important role in innate immunity via the oxidative burst, using the p47phox-and gp91 phox -containing NAD(P)H oxidase known as Nox2. In dextran sulphate sodium (DSS)-induced colitis, no significant difference in inflammation between p47 phoxÀ/À and wild-type (WT) mice was reported, but there was improved endothelium-dependent arteriolar dilation in gp91 phoxÀ/À mice, compared with that in WT mice. Gp91 phox and p47 phox are not only essential components of phagocyte Nox2, but also have roles in other enzymes. Thus the differences in response of their respective gene knockout mice to DSS challenge are not completely unexpected, but need further investigation. The clinicopathological changes and immunological responses to DSS challenge have not been fully described in gp91 phoxÀ/À mice. Thus we treated WT and gp91 phoxÀ/À mice with 2.5% DSS for 7 days. The gp91 phoxÀ/À mice developed less severe colitis than WT mice following DSS treatment, reflected by a smaller body weight loss, less rectal bleeding and fewer histopathological changes. Less colonic myeloperoxidase was observed in gp91 phoxÀ/À , compared with WT mice, following DSS challenge, correlating with interleukin (IL)-6 production. IL-10 was upregulated in both gp91 phoxÀ/À and WT mice, but was significantly higher in the latter, following 7 days DSS challenge. These results suggest that gp91 phoxÀ/À mice are less susceptible to acute DSS-induced colitis, possibly because of a reduced oxidative burst in the intestine and, consequently, less tissue damage.

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Genetic Analysis of Susceptibility to Dextran Sulfate Sodium-Induced Colitis in Mice

Cited by 93 publications

References 51 publications

Increased sensitivity to dextran sodium sulfate colitis in IRE1β-deficient mice

Increased sensitivity to dextran sodium sulfate colitis in IRE1β-deficient mice

Integrative Genetic Analysis of Allergic Inflammation in the Murine Lung

Gp91^phox contributes to the development of experimental inflammatory bowel disease

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Genetic Analysis of Susceptibility to Dextran Sulfate Sodium-Induced Colitis in Mice

Cited by 93 publications

References 51 publications

Increased sensitivity to dextran sodium sulfate colitis in IRE1β-deficient mice

Increased sensitivity to dextran sodium sulfate colitis in IRE1β-deficient mice

Integrative Genetic Analysis of Allergic Inflammation in the Murine Lung

Gp91phox contributes to the development of experimental inflammatory bowel disease

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Gp91^phox contributes to the development of experimental inflammatory bowel disease