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      MicroRNA-21 Knockout Improve the Survival Rate in DSS Induced Fatal Colitis through Protecting against Inflammation and Tissue Injury

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          Abstract

          Background

          MicroRNA-21 (miR-21) is overexpressed in most inflammatory diseases, but its physiological role in gut inflammation and tissue injury is poorly understood. The goal of this work is to understand the role of miR-21 in colitis and damage progression of intestine in a genetically modified murine model.

          Methods

          Experimental colitis was induced in miR-21 KO and wild-type (WT) mice by 3.5% dextran sulphate sodium (DSS) administration for 7 days. Disease activity index(DAI), blood parameters, intestinal permeability, histopathologic injury, cytokine and chemokine production, and epithelial cells apoptosis were examined in colons of miR-21 KO and WT mice.

          Results

          miR-21 was overexpressed in intestine of inflammatory bowel diseases (IBD) and acute intestinal obstruction (AIO) patients when compared with normal intestinal tissues. Likewise, miR-21 was up-regulated in colon of IL-10 KO mice when compared with control mice. WT mice rapidly lost weight and were moribund 5 days after treatment with 3.5% DSS, while miR-21 KO mice survived for at least 6 days. Elevated leukocytes and more severe histopathology were observed in WT mice when compared with miR-21 KO mice. Elevated levels of TNF-α and macrophage inflammatory protein-2(MIP-2) in colon culture supernatants from WT mice exhibited significant higher than miR-21 KO mice. Furthermore, CD3 and CD68 positive cells, intestinal permeability and apoptosis of epithelial cells were significantly increased in WT mice when compared with miR-21 KO mice. Finally, we found that miR-21 regulated the intestinal barrier function through modulating the expression of RhoB and CDC42.

          Conclusion

          Our results suggest that miR-21 is overexpressed in intestinal inflammation and tissue injury, while knockout of miR-21 in mice improve the survival rate in DSS-induced fatal colitis through protecting against inflammation and tissue injury. Therefore, attenuated expression of miR-21 in gut may prevent the onset or progression of inflammatory bowel disease in patients.

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          Most cited references35

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          MicroRNA-21 is an antiapoptotic factor in human glioblastoma cells.

          Jennifer A. Chan, Anna Krichevsky, Kenneth S. Kosik (2005)
          MicroRNAs (miRNAs) are small noncoding RNA molecules that regulate protein expression by targeting the mRNA of protein-coding genes for either cleavage or repression of translation. The roles of miRNAs in lineage determination and proliferation as well as the location of several miRNA genes at sites of translocation breakpoints or deletions has led to the speculation that miRNAs could be important factors in the development or maintenance of the neoplastic state. Here we show that the highly malignant human brain tumor, glioblastoma, strongly over-expresses a specific miRNA, miR-21. Our studies show markedly elevated miR-21 levels in human glioblastoma tumor tissues, early-passage glioblastoma cultures, and in six established glioblastoma cell lines (A172, U87, U373, LN229, LN428, and LN308) compared with nonneoplastic fetal and adult brain tissues and compared with cultured nonneoplastic glial cells. Knockdown of miR-21 in cultured glioblastoma cells triggers activation of caspases and leads to increased apoptotic cell death. Our data suggest that aberrantly expressed miR-21 may contribute to the malignant phenotype by blocking expression of critical apoptosis-related genes.
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            Negative regulation of TLR4 via targeting of the proinflammatory tumor suppressor PDCD4 by the microRNA miR-21.

            Frederick J. Sheedy, Eva M. Pålsson-McDermott, Elizabeth J Hennessy … (2010)
            The tumor suppressor PDCD4 is a proinflammatory protein that promotes activation of the transcription factor NF-kappaB and suppresses interleukin 10 (IL-10). Here we found that mice deficient in PDCD4 were protected from lipopolysaccharide (LPS)-induced death. The induction of NF-kappaB and IL-6 by LPS required PDCD4, whereas LPS enhanced IL-10 induction in cells lacking PDCD4. Treatment of human peripheral blood mononuclear cells with LPS resulted in lower PDCD4 expression, which was due to induction of the microRNA miR-21 via the adaptor MyD88 and NF-kappaB. Transfection of cells with a miR-21 precursor blocked NF-kappaB activity and promoted IL-10 production in response to LPS, whereas transfection with antisense oligonucleotides to miR-21 or targeted protection of the miR-21 site in Pdcd4 mRNA had the opposite effect. Thus, miR-21 regulates PDCD4 expression after LPS stimulation.
            Article 0 comments Cited 353 times – based on 0 reviews     Review now
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              Increased expression of interleukin 17 in inflammatory bowel disease.

              S Fujino, A Andoh, S Bamba … (2003)
              Interleukin (IL) 17 is a cytokine which exerts strong proinflammatory activities. In this study we evaluated changes in IL-17 expression in the inflamed mucosa and in the serum of patients with inflammatory bowel disease (IBD). Tissue samples were obtained endoscopically or surgically from patients with ulcerative colitis (UC) (n=20), Crohn's disease (CD) (n=20), infectious colitis (n=5), ischaemic colitis (n=8), and normal colorectal tissues (n=15). IL-17 expression was evaluated by a standard immunohistochemical procedure. Serum IL-17 levels were determined by ELISA. IL-17 mRNA expression was analysed by reverse transcriptase-polymerase chain reaction. IL-17 expression was not detected in samples from normal colonic mucosa, infectious colitis, or ischaemic colitis. In the inflamed mucosa of active UC and CD patients, IL-17 expression was clearly detectable in CD3(+) T cells or CD68(+) monocytes/macrophages. The average number of IL-17(+) cells was significantly increased in active UC and CD patients compared with inactive patients. IL-17 mRNA expression was not detected in normal mucosa but was detectable in the mucosa from active UC and CD patients. IL-17 was not detected in the sera from normal individuals, infectious colitis, or ischaemic colitis patients but IL-17 levels were significantly elevated in IBD patients. IL-17 expression in the mucosa and serum was increased in IBD patients. It is likely that IL-17 expression in IBD may be associated with altered immune and inflammatory responses in the intestinal mucosa.
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                Author and article information

                Contributors
                Markus M. Heimesaat: Role: Editor
                Journal
                Journal ID (nlm-ta): PLoS One
                Journal ID (iso-abbrev): PLoS ONE
                Journal ID (publisher-id): plos
                Journal ID (pmc): plosone
                Title: PLoS ONE
                Publisher: Public Library of Science (San Francisco, USA )
                ISSN (Electronic): 1932-6203
                Publication date Collection: 2013
                Publication date (Electronic): 24 June 2013
                Volume: 8
                Issue: 6
                Electronic Location Identifier: e66814
                Affiliations
                [1]Department of General Surgery, Affiliated Sixth People’s Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai Jiao Tong University, Shanghai, China
                Charité, Campus Benjamin Franklin, Germany
                Author notes

                Competing Interests: The authors have declared that no competing interests exist.

                Conceived and designed the experiments: CZS HLQ. Performed the experiments: CZS YL JY YX HC HH YY WW RG HLQ. Analyzed the data: CZS YL. Contributed reagents/materials/analysis tools: CZS YL HLQ. Wrote the paper: CZS HLQ.

                Article
                Publisher ID: PONE-D-13-08734
                DOI: 10.1371/journal.pone.0066814
                PMC ID: 3691313
                PubMed ID: 23826144
                SO-VID: 04e42f19-d357-4773-881a-2ca11307fb48
                Copyright statement: Copyright @ 2013
                License:

                This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

                History
                Date received : 16 February 2013
                Date accepted : 8 May 2013
                Page count
                Pages: 12
                Funding
                This work was supported by grants from National Natural Science Foundation Key projects of China (No.81230057), National Natural Science Foundation of China (No. 81172325), and the Major Basic Research Program of Shanghai (No 12DZ1930502). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
                Categories
                Subject: Research Article
                Subject: Biology
                Subject: Anatomy and Physiology
                Subject: Digestive System
                Subject: Digestive Physiology
                Subject: Biochemistry
                Subject: Nucleic Acids
                Subject: RNA
                Subject: Genetics
                Subject: Animal Genetics
                Subject: Gene Function
                Subject: Human Genetics
                Subject: Model Organisms
                Subject: Animal Models
                Subject: Mouse
                Subject: Medicine
                Subject: Clinical Research Design
                Subject: Animal Models of Disease
                Subject: Gastroenterology and Hepatology
                Subject: Inflammatory Bowel Disease

                ScienceOpen disciplines: Uncategorized
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                ScienceOpen disciplines: Uncategorized

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