Colitis locus on chromosome 2 impacting the severity of early-onset disease in mice deficient in GPX1 and GPX2

Esworthy, R. Steven; Kim, Byung‐Wook; Larson, Garrett P.; Yip, M.L. Richard; Smith, David; Li, Min; Chu, Fong‐Fong

doi:10.1002/ibd.21479

Cited by 29 publications

(51 citation statements)

References 53 publications

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“…Within the ileum, no marked regional variation in pathology is noted in the diseased mice by 35 days of age. In the large intestine, the cecum shows pathology, while the upper colon has mild or no pathology, and the rectum has the strongest pathology [33], [34]. For sample collection, 1 cm of the distal ileum (ileocecal junction) and rectum was immersed in RNAlater (Life Technologies) and processed for RNA isolation.…”

Section: Methodsmentioning

confidence: 99%

Deficiency in Duox2 activity alleviates ileitis in GPx1- and GPx2-knockout mice without affecting apoptosis incidence in the crypt epithelium

et al. 2017

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Mice deficient in glutathione peroxidase (GPx)-1 and -2 (GPx1-/-GPx2-/- double knockout or DKO mice) develop very-early-onset (VEO) ileocolitis, suggesting that lack of defense against reactive oxygen species (ROS) renders susceptibility to intestinal inflammation. Two members of ROS-generating NADPH oxidase family, NOX1 and DUOX2, are highly inducible in the intestinal epithelium. Previously, we reported that Nox1 deficiency ameliorated the pathology in DKO mice (Nox1-TKO). The role of Duox2 in ileocolitis of the DKO mice is evaluated here in Duoxa-TKO mice by breeding DKO mice with Duoxa-/- mice (Duoxa-TKO), which do not have Duox2 activity. Similar to Nox1-TKO mice, Duoxa-TKO mice no longer have growth retardation, shortened intestine, exfoliation of crypt epithelium, crypt abscesses and depletion of goblet cells manifested in DKO mice by 35 days of age. Unlike Nox1-TKO mice, Duoxa-TKO mice still have rampant crypt apoptosis, elevated proliferation, partial loss of Paneth cells and diminished crypt density. Treating DKO mice with NOX inhibitors (di-2-thienyliodonium/DTI and thioridazine/THZ) and an antioxidant (mitoquinone/MitoQ) significantly reduced gut pathology. Furthermore, in the inflamed human colon, DUOX protein expression is highly elevated in the apical, lateral and perinuclear membrane along the whole length of gland. Taken together, we conclude that exfoliation of crypt epithelium, but not crypt apoptosis, is a major contributor to inflammation. Both Nox1 and Duox2 induce exfoliation of crypt epithelium, but only Nox1 induces apoptosis. NOX1 and DUOX2 may be potential therapeutic targets for treating ileocolitis in human patients suffering inflammatory bowel disease (IBD).

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Section: Methodsmentioning

confidence: 99%

Deficiency in Duox2 activity alleviates ileitis in GPx1- and GPx2-knockout mice without affecting apoptosis incidence in the crypt epithelium

et al. 2017

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“…We also correlated Lpo DNA methylation with inflammation (without DSS treatment) by comparing DNA methylation levels between 129 DKO colon and a congenic 129-Gdac1 B6 DKO colon, which had milder colitis [11] to remove the strain, GPx status, and age variables. Again, the fact that the 129 DKO colon had a higher Saa3 mRNA levels, an inflammation marker, than the congenic 129-Gdac1 B6 DKO colon supports its higher inflammation levels in the 129 DKO colon (Figure 7C).…”

Section: Resultsmentioning

confidence: 99%

“…B6 (≥N7) GPx1/2 DKO and WT mice and 129 (≥N7) DKO and non-DKO mice were maintained in ventilated cages with free access to food and water. A 129 congenic line with B6 Gdac1 locus, 129-Gdac1 B6 mice, were generated [11]. The congenic 129-Gdac1 B6 DKO mice had milder colitis than 129 DKO mice.…”

Section: Methodsmentioning

confidence: 99%

“…We have reported that the intestinal epithelial cells isolated from C57BL/6J (B6) mice deficient in two glutathione peroxidases, GPx1 and GPx2, have aberrant global CpG island methylation pattern compared to non-DKO control ileum [10]. GPx1/2-double knockout (DKO) mice have spontaneous ileocolitis, where disease severity is strain-dependent; B6 and 129S1/SvlmJ (129) DKO have mild and severe disease, respectively [11]. Shown by CpG-island microarrays, ~250 genes, including the Lpo intragenic CpG island, in B6 DKO mice have aberrant hypermethylation [10].…”

Section: Introductionmentioning

confidence: 99%

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Expression of lactoperoxidase in differentiated mouse colon epithelial cells

Kim

Esworthy

Hahn

et al. 2012

Free Radical Biology and Medicine

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Lactoperoxidase (LPO) is known to be present in secreted fluids, such as milk and saliva. Functionally, LPO teams up with dual oxidases (DUOXs) to generate bactericidal hypothiocyanite in the presence of thiocyanate. DUOX2 is expressed in intestinal epithelium, but there is little information on LPO expression in this tissue. To fill the gap of knowledge, we have analyzed Lpo gene expression and its regulation in mouse intestine. In wild-type (WT) C57BL/6 (B6) mouse intestine, an appreciable level of mouse Lpo gene expression was detected in the colon, but not the ileum. However, in the B6 mice deficient in glutathione peroxidase (GPx)-1 and -2, GPx1/2-double knockout (DKO), which had intestinal pathology, the colon Lpo mRNA levels increased 5- to 12-fold depending on mouse age. The Lpo mRNA levels in WT and DKO 129S1/SvlmJ (129) colon were even higher, 9- and 5-fold, than B6 DKO colon. Higher levels of Lpo protein and enzymatic activity were also detected in the 129 mouse colon than B6 colon. Lpo protein was expressed in the differentiated colon epithelial cells, away from crypt base, as shown by immunohistochemistry. Similar to human LPO mRNA, mouse Lpo mRNA had multiple spliced forms, although only the full-length variant 1 (V1) was translated. Higher methylation was found in 129 than B6 strain, DKO than control colon, and older than juvenile mice. However, methylation of Lpo intragenic CpG island was not directly induced by inflammation, since dextran sulfate sodium (DSS)-induced colitis did not increase DNA methylation in B6 DKO colon. Also, Lpo DNA methylation is not correlated with gene expression.

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“…The sections from the distal third of colon were scored for inflammation pathology using an 11-point system modified from our previous studies [40,41]. These include lymphocyte and neutrophil infiltration (0-3 points), Paneth cell or goblet cell degranulation (0-2 points), epithelium reactivity, such as crypt distortion (0-3 points) and inflammatory foci (0-3 points).…”

Section: Analysis Of Mouse Colon Histology By Hematoxylin and Eosin (mentioning

confidence: 99%

Mice Deficient in Cyp4a14 Have An Increased Number of Goblet Cells and Attenuated Dextran Sulfate Sodium-Induced Colitis

Xuan¹,

Zhou²,

Tan³

et al. 2018

Cell Physiol Biochem

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Background/Aims: Cyp4a14 is a member of cytochrome P450 (Cyp450) enzyme superfamily that possesses NADPH monooxygenase activity, which catalyzes omega-hydroxylation of medium-chain fatty acids and arachidonic acid. Study suggests that down-regulation of Cyp4a14 has an anti-inflammatory response in intestine. The present study was to test the function of Cyp4a14 in dextran sulfate sodium (DSS)-induced colitis. Methods: Female Cyp4a14-knockout (KO) and wild-type (WT) mice were treated with DSS for 6 days to induce colitis. The colon of mice was histologically observed by hematoxylin and eosin (H&E) and periodic acid Schiff (PAS) staining. The serum malondialdehyde (MDA), an endogenous indicator of oxidative stress, was chemically measured. Proinflammatory and NADPH oxidase genes were examined by quantitative polymerase chain reaction (qPCR). Results: Cyp4a14-KO mice had a significantly higher number of goblet cells in the colon and were more resistant to DSS-induced colitis compared with the WT mice. The DSS-treated KO mice had lower levels of MDA. Consistent with the milder inflammatory pathological changes, DSS-treated KO mice had lower levels of IL-1β, IL-6 and TNF-α mRNA in the liver and the colon. Moreover, the colon of DSS-treated Cyp4a14-KO and WT mice had higher mRNA levels of two members of NADPH oxidases, Nox2 and Nox4, suggesting that both Nox2 and Nox4 are inflammatory markers. By contrast, DSS-treated WT and KO mice had drastically decreased epithelium-localized Nox1 and dual oxidase (Duox) 2 mRNA levels, coinciding with the erosion of the mucosa induced by DSS. Conclusion: These results suggests a hypothesis that the increased goblet cell in the colon of Cyp4a14-KO mice provides protection from mucosal injury and Cyp4a14-increased oxidative stress exacerbates DSS-induced colitis. Therefore, Cyp4a14 may represent a potential target for treating colitis.

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Colitis locus on chromosome 2 impacting the severity of early-onset disease in mice deficient in GPX1 and GPX2

Cited by 29 publications

References 53 publications

Deficiency in Duox2 activity alleviates ileitis in GPx1- and GPx2-knockout mice without affecting apoptosis incidence in the crypt epithelium

Deficiency in Duox2 activity alleviates ileitis in GPx1- and GPx2-knockout mice without affecting apoptosis incidence in the crypt epithelium

Expression of lactoperoxidase in differentiated mouse colon epithelial cells

Mice Deficient in Cyp4a14 Have An Increased Number of Goblet Cells and Attenuated Dextran Sulfate Sodium-Induced Colitis

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