MicroRNA-146b improves intestinal injury in mouse colitis by activating NF-kB and improving epithelial barrier function
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ABSTRACT:
ORGANISM(S): Rattus norvegicus Mus musculus Homo sapiens
PROVIDER: GSE40708 | GEO | 2012/09/10
SECONDARY ACCESSION(S): PRJNA174740
REPOSITORIES: GEO
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Project description:Aim: The precise role of microRNAs in inflammatory disease has been less clear. The present study investigated the effect of microRNA (miR-146b) on improving intestinal inflammation. Methods: The microRNA profile in IL-10-deficient mice was examined using microRNA arrays and miR-146b was selected for the following experiments. The expression vectors containing either the whole sequence of miR-146b or its siRNA were intraperitoneally administered to the dextran sulfate sodium (DSS)-induced colitis mouse. Results: The overexpression of miR-146b activated the NF-kB pathway, improved the epithelial barrier function, relieved intestinal inflammation in the DSS-induced colitis mice, and improved the survival rate of mice with lethal colitis. Furthermore, this amelioration of the intestinal inflammation by miR-146b was negated by the inhibitor for NF-kB pathway. Conclusion: The modulation of miR-146b expression is a potentially useful therapy for the treatment of intestinal inflammation through the activation of the NF-kB pathway. Mice: The present studies were approved by the Institutional Animal Care and Use Committee of the Asahikawa Medical College. C57BL/6 and IL-10-/- mice were purchased from Sankyo Labo Service Co., Inc. (Tokyo, Japan) and Jackson Laboratories (Bar Harbor, ME), respectively. Large intestines with or without treatments were removed, rinsed with saline, and the epithelium was gently sheared off with glass slides for protein determination. microRNA arrays: RNA was extracted from the large intestines of mice with Trizol and then was immediately frozen in liquid nitrogen. Next, the microRNA expression profiles of large intestine in wild-type and IL-10-deficient mouse were investigated using the mirVanaTM miRNA bioarray (Filgene, Inc., Japan). Any more than 2-fold differences were considered to indicate a significant change.
2012-09-10 | E-GEOD-40708 | biostudies-arrayexpress
Project description:The canonical NF-kB module induces nuclear translocation of RelA heterodimers from the latent cytoplasmic complexes. RelA directs inflammatory immune responses against microbial entities. However, aberrant RelA activity also triggers destructive inflammation, including those associated with inflammatory bowel disease (IBD). What provokes this pathological RelA activity remains unclear. As such, the noncanonical NF-kB pathway activates RelB heterodimers and mediates immune organogenesis. Because NF-kB-activating pathways are interlinked, we asked if noncanonical NF-kB signaling exacerbated intestinal inflammation. Our investigation revealed recurrent engagement of the noncanonical pathway in human IBD. In a mouse model of chemical colitis, the noncanonical NF-kB signaling gene Nfkb2 aggravated inflammation by amplifying the RelA activity induced in intestinal epithelial cells. Our mechanistic studies clarified that noncanonical signaling augmented the abundance of latent RelA complexes leading to hyperactive canonical NF-kB response in the colitogenic gut. In sum, latent dimer homeostasis appears to link noncanonical NF-kB signaling to RelA-driven inflammatory pathologies.
2021-07-07 | GSE148577 | GEO
Project description:Aberrant intestinal inflammation plays a critical role in the development of colitis-associated colorectal cancer (CAC), yet the mechanisms behind this progression are not clearly defined. While altered microRNA (miRNA) expression is observed in CAC, it is unclear how myeloid-specific microRNA’s impact on the inflammatory process that underpins the continuum from Ulcerative colitis (UC) to tumorigenesis. Here we used the Azoxymethane-Dextran Sodium Sulfate (AOM-DSS) (10mg/kg) model of CAC on miR-223-/y and WT mice, with an overall aim of identifying differences in their expression profiles following AOM/DSS treatment.
2024-10-01 | GSE245724 | GEO
Project description:Background: MicroRNAs (miRNAs) acting as negative regulators of gene expression are differentially expressed in intestinal tissues of patients with inflammatory bowel disease (IBD). Assessing the functional role of miRNAs in murine models of colitis facilitates elucidating the role of specific miRNAs in human IBD. The aim of this study was to determine the miRNA signature of murine models of colitis and to assess the influence of miR-21 on intestinal inflammation. Methods: miRNAs expression was accessed by microarray for acute and chronic murine model of colitis induced by DSS or TNBS. miR-21-deficient mouse and littermates controls were assessed in the standard DSS, TNBS and CD4+ T cell transfer models of colitis. RNAs of mouse colon and CD4+CD45RBHigh cells were analyzed by miRNA and mRNA microarray, and quantitative RT-PCR. Th1 polarization was accessed by flow-cytometry and ELISA. Results: Alterations of in miRNAs expression were identified for acute and chronic DSS colitis and TNBS colitis, receptively. The Expression of miRs-21, -142-3p and -223 was were distinct between DSS and TNBS models while overlap of numerous miRNAs was seen. Importantly, miRs-19b, -192 and -215, that are decreased in IBD, were significantly decreased in all 4 models of colitis. miR-21, which is increased in IBD, was increased in TNBS colitis but not the DSS colitis models. Further assessment of the miR-21-deficient 1-/- mice revealed that the deletion of miR-21 results in the exacerbation of both the TNBS and T cell-transfer models of colitis. Conclusions: miRNAs are differentially expressed in both human IBD and murine colitis, with overlap of several IBD-associated miRNAs. The demonstration that miR-21 deletion exacerbated CD4+ T cell-mediated models of colitis provides further evidence that miRNAs play significant roles in the pathogenesis of IBD. miRNAs expression was accesed for acute and chronic murine model of colitis induced by DSS or TNBS.Total of 20 samples with duplicates were analyed in this study.
2014-07-23 | E-GEOD-59650 | biostudies-arrayexpress
Project description:Background: MicroRNAs (miRNAs) acting as negative regulators of gene expression are differentially expressed in intestinal tissues of patients with inflammatory bowel disease (IBD). Assessing the functional role of miRNAs in murine models of colitis facilitates elucidating the role of specific miRNAs in human IBD. The aim of this study was to determine the miRNA signature of murine models of colitis and to assess the influence of miR-21 on intestinal inflammation. Methods: miRNAs expression was accessed by microarray for acute and chronic murine model of colitis induced by DSS or TNBS. miR-21-deficient mouse and littermates controls were assessed in the standard DSS, TNBS and CD4+ T cell transfer models of colitis. RNAs of mouse colon and CD4+CD45RBHigh cells were analyzed by miRNA and mRNA microarray, and quantitative RT-PCR. Th1 polarization was accessed by flow-cytometry and ELISA. Results: Alterations of in miRNAs expression were identified for acute and chronic DSS colitis and TNBS colitis, receptively. The Expression of miRs-21, -142-3p and -223 was were distinct between DSS and TNBS models while overlap of numerous miRNAs was seen. Importantly, miRs-19b, -192 and -215, that are decreased in IBD, were significantly decreased in all 4 models of colitis. miR-21, which is increased in IBD, was increased in TNBS colitis but not the DSS colitis models. Further assessment of the miR-21-deficient 1-/- mice revealed that the deletion of miR-21 results in the exacerbation of both the TNBS and T cell-transfer models of colitis. Conclusions: miRNAs are differentially expressed in both human IBD and murine colitis, with overlap of several IBD-associated miRNAs. The demonstration that miR-21 deletion exacerbated CD4+ T cell-mediated models of colitis provides further evidence that miRNAs play significant roles in the pathogenesis of IBD. miRNAs expression was accesed for acute and chronic murine model of colitis induced by DSS or TNBS.Total of 20 samples with duplicates were analyed in this study.
2014-07-23 | E-GEOD-59649 | biostudies-arrayexpress
Project description:Inflammatory bowel disease (IBD), comprising CrohnM-BM-4s disease and Ulcerative colitis, is characterized by chronic relapsing inflammation of the gut. It has been shown that increased proteasomal activity is associated with the expression of immunoproteasomes, which enhances NF-kB activation and thus promotes inflammation in IBD-patients. Here, we investigate whether modulation of the proteasomal activity is a suitable therapeutic approach to limit inflammation in colitis. This concept was tested in two different experimental setups. First, development of dextran sulfate sodium (DSS)-induced colitis was tested in lmp7-/--mice, which lack the essential immunoproteasome-subunit LMP7 or in wildtype-mice treated with the proteasome inhibitor bortezomib. Compared to WT mice, lmp7-/- mice revealed significantly attenuated colitis resulting from reduced NF-kB activation in the absence of LMP7. Further, treatment with bortezomib revealed dose-dependent amelioration of DSS-induced inflammation. In both approaches proteasome modulation limited the infiltration of neutrophils, consequently reducing tissue damage. In summary our experiments demonstrate that modulation of the proteasomal activity is effective in attenuating experimental colitis. In particular, our data suggest that the immunoproteasome-subunit LMP7 is a suitable target for the therapy of IBD. Microarray experiments were performed as dual-color hybridizations. To compensate for dye-specific effects, a dye-reversal color-swap was applied. Samples of proximal colon were cut longitudinally, washed in PBS, shortly incubated in 4M Guanidinium-isothiocyanat and transferred to TRIzol (Invitrogen).
2010-07-06 | E-GEOD-18163 | biostudies-arrayexpress
Project description:Background: MicroRNAs (miRNAs) acting as negative regulators of gene expression are differentially expressed in intestinal tissues of patients with inflammatory bowel disease (IBD). Assessing the functional role of miRNAs in murine models of colitis facilitates elucidating the role of specific miRNAs in human IBD. The aim of this study was to determine the miRNA signature of murine models of colitis and to assess the influence of miR-21 on intestinal inflammation. Methods: miRNAs expression was accessed by microarray for acute and chronic murine model of colitis induced by DSS or TNBS. miR-21-deficient mouse and littermates controls were assessed in the standard DSS, TNBS and CD4+ T cell transfer models of colitis. RNAs of mouse colon and CD4+CD45RBHigh cells were analyzed by miRNA and mRNA microarray, and quantitative RT-PCR. Th1 polarization was accessed by flow-cytometry and ELISA. Results: Alterations of in miRNAs expression were identified for acute and chronic DSS colitis and TNBS colitis, receptively. The Expression of miRs-21, -142-3p and -223 was were distinct between DSS and TNBS models while overlap of numerous miRNAs was seen. Importantly, miRs-19b, -192 and -215, that are decreased in IBD, were significantly decreased in all 4 models of colitis. miR-21, which is increased in IBD, was increased in TNBS colitis but not the DSS colitis models. Further assessment of the miR-21-deficient 1-/- mice revealed that the deletion of miR-21 results in the exacerbation of both the TNBS and T cell-transfer models of colitis. Conclusions: miRNAs are differentially expressed in both human IBD and murine colitis, with overlap of several IBD-associated miRNAs. The demonstration that miR-21 deletion exacerbated CD4+ T cell-mediated models of colitis provides further evidence that miRNAs play significant roles in the pathogenesis of IBD. Gene expression profiles were established for normal miR-21-/- mice and wild type c57BL/6 mice (WT). Total of 6 samples with replicates were included in this study.
2014-07-23 | E-GEOD-59648 | biostudies-arrayexpress
Project description:Inflammatory bowel disease (IBD), comprising Crohn´s disease and Ulcerative colitis, is characterized by chronic relapsing inflammation of the gut. It has been shown that increased proteasomal activity is associated with the expression of immunoproteasomes, which enhances NF-kB activation and thus promotes inflammation in IBD-patients. Here, we investigate whether modulation of the proteasomal activity is a suitable therapeutic approach to limit inflammation in colitis. This concept was tested in two different experimental setups. First, development of dextran sulfate sodium (DSS)-induced colitis was tested in lmp7-/--mice, which lack the essential immunoproteasome-subunit LMP7 or in wildtype-mice treated with the proteasome inhibitor bortezomib. Compared to WT mice, lmp7-/- mice revealed significantly attenuated colitis resulting from reduced NF-kB activation in the absence of LMP7. Further, treatment with bortezomib revealed dose-dependent amelioration of DSS-induced inflammation. In both approaches proteasome modulation limited the infiltration of neutrophils, consequently reducing tissue damage. In summary our experiments demonstrate that modulation of the proteasomal activity is effective in attenuating experimental colitis. In particular, our data suggest that the immunoproteasome-subunit LMP7 is a suitable target for the therapy of IBD.
2010-07-07 | GSE18163 | GEO
Project description:microRNA-146b improves intestinal injury in mouse colitis by activating NF-kB and improving epithelial barrier function
| PRJNA174740 | ENA
Project description:Background: MicroRNAs (miRNAs) acting as negative regulators of gene expression are differentially expressed in intestinal tissues of patients with inflammatory bowel disease (IBD). Assessing the functional role of miRNAs in murine models of colitis facilitates elucidating the role of specific miRNAs in human IBD. The aim of this study was to determine the miRNA signature of murine models of colitis and to assess the influence of miR-21 on intestinal inflammation. Methods: miRNAs expression was accessed by microarray for acute and chronic murine model of colitis induced by DSS or TNBS. miR-21-deficient mouse and littermates controls were assessed in the standard DSS, TNBS and CD4+ T cell transfer models of colitis. RNAs of mouse colon and CD4+CD45RBHigh cells were analyzed by miRNA and mRNA microarray, and quantitative RT-PCR. Th1 polarization was accessed by flow-cytometry and ELISA. Results: Alterations of in miRNAs expression were identified for acute and chronic DSS colitis and TNBS colitis, receptively. The Expression of miRs-21, -142-3p and -223 was were distinct between DSS and TNBS models while overlap of numerous miRNAs was seen. Importantly, miRs-19b, -192 and -215, that are decreased in IBD, were significantly decreased in all 4 models of colitis. miR-21, which is increased in IBD, was increased in TNBS colitis but not the DSS colitis models. Further assessment of the miR-21-deficient 1-/- mice revealed that the deletion of miR-21 results in the exacerbation of both the TNBS and T cell-transfer models of colitis. Conclusions: miRNAs are differentially expressed in both human IBD and murine colitis, with overlap of several IBD-associated miRNAs. The demonstration that miR-21 deletion exacerbated CD4+ T cell-mediated models of colitis provides further evidence that miRNAs play significant roles in the pathogenesis of IBD.
2014-07-23 | GSE59650 | GEO