Nox1 causes ileocolitis in mice deficient in glutathione peroxidase-1 and -2 |
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| Affiliation: | 1. Department of Radiation Biology and Beckman Research Institute, City of Hope, Duarte, CA 91010, USA;2. Irell & Manella Graduate School of Biological Sciences, Beckman Research Institute, City of Hope, Duarte, CA 91010, USA;3. National Cancer Institute, Bethesda, MD 20816, USA;1. College of Pharmacy & Medical Research Center, Chungbuk National University, Chungbuk 361-763, Republic of Korea;2. Research Center for Cell Fate Control, College of Pharmacy, Sookmyung Women׳s University, Seoul 140-742, Republic of Korea;3. Department of Bioscience and Biotechnology, Bio/Molecular Informatics Center, Konkuk University, Seoul 150-716, Republic of Korea;1. Department of Laboratory Medicine, Third Xiangya Hospital, Central South University, Changsha, China;2. Center of Clinical Laboratory, Hunan Children’s Hospital, Changsha, China;3. Department of Pharmacol, Xiangya Hospital, Central South University, Changsha, China;4. Department of Physiology, Xiangya School of Medicine, Central South University, Changsha, China;5. Department of Hepatobiliary Surgery, Hunan Provincial People’s Hospital, Hunan Normal University, Changsha, China;6. School of Pharmaceutical Science, Dalian University of Technology, Creighton University Medical Center, Dalian, China;7. School of Laboratory Medicine and Life Sciences, Wenzhou Medical University, Wenzhou, China;1. Division of Gastroenterology, Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, Michigan;2. Unit for Laboratory Animal Medicine, University of Michigan Medical School, Ann Arbor, Michigan;1. Department of Molecular and Integrative Physiology, University of Michigan Medical School, Ann Arbor, MI 48109, USA;2. Department of Internal Medicine, Division of Gastroenterology, University of Michigan Medical School, Ann Arbor, MI 48109, USA;3. Department of Radiation Oncology, Perlmutter Cancer Center, NYU Langone Medical Center, New York, NY 10016, USA;1. 3rd Department of Medicine, 1st Faculty of Medicine, Charles University and General University Hospital, U Nemocnice 1, 12800 Prague 2, Czech Republic;2. Department of Anesthesia, Resuscitation and Intensive Medicine, 1st Faculty of Medicine, Charles University and General University Hospital, U Nemocnice 2, 12800 Prague 2, Czech Republic;3. Department of Cybernetics, Czech Technical University, Technicka 2, 16627 Prague 6, Czech Republic;4. Department of Pathophysiology, 1st Faculty of Medicine, Charles University and General University Hospital, U Nemocnice 2, 12800 Prague 2, Czech Republic;5. 2nd Department of Surgery – Department of Cardiovascular Surgery of the First Faculty of Medicine and General University Hospital, U Nemocnice 2, 12800 Prague 2, Czech Republic;1. Department of Gastroenterology, The First Affiliated Hospital of Nanchang University, Nanchang, 330006, Jiangxi, China;2. Department of Plastic and Cosmetic Surgery, The Second Affiliated Hospital of Nanchang University, Nanchang, 330006, Jiangxi, China |
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| Abstract: | We previously reported that mice deficient in two Se-dependent glutathione peroxidases, GPx1 and GPx2, have spontaneous ileocolitis. Disease severity depends on mouse genetic background. Whereas C57BL/6J (B6) GPx1/2-double-knockout (DKO) mice have moderate ileitis and mild colitis, 129S1Svlm/J (1 2 9) DKO mice have severe ileocolitis. Because GPx’s are antioxidant enzymes, we hypothesized that elevated reactive oxygen species trigger inflammation in these DKO mice. To test whether NADPH oxidase 1 (Nox1) contributes to colitis, we generated B6 triple-KO (TKO) mice to study their phenotype. Because the Nox1 gene is X-linked, we analyzed the effects of Nox1 on male B6 TKO mice and female B6 DKO mice with the Nox1+/− (het-TKO) genotype. We found that the male TKO and female het-TKO mice are virtually disease-free when monitored from 8 through 50 days of age. Male TKO and female het-TKO mice have nearly no signs of disease (e.g., lethargy and perianal alopecia) that are often exhibited in the DKO mice; further, the slower growth rate of DKO mice is almost completely eliminated in male TKO and female het-TKO mice. Male TKO and female het-TKO mice no longer have the shortened small intestine present in the DKO mice. Finally, the pathological characteristics of the DKO ileum, including the high level of crypt apoptosis (analyzed by apoptotic figures, TUNEL, and cleaved caspase-3 immunohistochemical staining), high numbers of Ki-67-positive crypt epithelium cells, and elevated levels of monocytes expressing myeloperoxidase, are all significantly decreased in male TKO mice. The attenuated ileal and colonic pathology is also evident in female het-DKO mice. Furthermore, the male DKO ileum has eightfold higher TNF cytokine levels than TKO ileum. Nox1 mRNA is highly elevated in both B6 and 129 DKO ileum compared to wild-type mouse ileum. Taking these results together, we propose that ileocolitis in the DKO mice is caused by Nox1, which is induced by TNF. The milder disease in female het-TKO intestine is probably due to random or imprinted X-chromosome inactivation, which produces mosaic Nox1 expression. |
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| Keywords: | Apoptosis C57BL/6J Glutathione peroxidase Inflammatory bowel disease NADPH oxidase Mouse ileum Mouse colon TNF Free radicals |
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