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Gene expression profiles of sclerosing cholangitis activity in mice

ABSTRACT: Background. Abcb4 (-/-) mice secrete phosphatidylcholine-deficient bile and develop sclerosing cholangitis (SC). The cholangitis involves differential hepatic transcription of genes whose products govern inflammation, activation of hepatic stellate cells and fibrosis. This study was undertaken to test the hypothesis that several genes involved in regulation of tissue inflammation and fibrosis display transcription rates that reflect SC disease activity. Methods. Abcb4 (-/-) mice fed cholic acid (CA) display high SC activity and ursodeoxycholic acid (UDCA) fed mice display low SC activity. Differential hepatic transcription of genes was accordingly measured in abcb4 (-/-) mice maintained on CA- and UDCA-supplemented diets using cDNA microarrays. Abcb4 (+/+) mice served as controls. The differential transcription of selected genes was verified by real time polymerase chain reaction. Liver tissue pathology was quantified by histopathology scoring and immunohistochemistry to visualize bile duct cells and activated hepatic stellate cells. Results. Differential transcription of Ccl2, Ccl20, Cxcl10, Nfκb1, Nfκb2, Tgfβ1, Tgfβ2, Sparc, Ctgf, Lgals3, Elf3, Spp1, Pdgfa, Pdgfrb, Col1a1, Col1a2 and Col4a1 genes paralleled the differing SC activities of cholic acid- and UDCA-fed abcb4 (-/-) mice. Histopathology scores and immunohistochemistry showed greatly enhanced activation of hepatic stellate cells during high SC activity due to CA feeding. Conclusion. Differential transcription of several genes relating to tissue inflammation and hepatic stellate cell activation parallels SC activity in abcb4 (-/-) mice. Data on their differential transcription may be used to gauge SC disease activity.

ORGANISM(S): Mus musculus

PROVIDER: GSE11507 | GEO | 2008/08/20

SECONDARY ACCESSION(S): PRJNA106333

REPOSITORIES: GEO

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Project description:Molecular factors governing liver pathology in abcb4 (-/-) mice. Dr. Nakken, Karl Esten, Dr. Berge, Knut E., Dr. Knut J. Labori, StÃ¥le NygÃ¥rd, Dr. Terese Haaland , professor Morten G. RÃ¦der. Institute for Experimental Medical Research and Department of Pathology, Ulleval University Hospital, Oslo, Norway and Institute for Medical Genetics, National Hospital, Oslo, Norway; E-mail: k.e.nakken@medisin.uio.no. Background and Aims: Abcb4 (mdr2) (-/-) mice secrete phosphatidylcholine-free bile and develop chronic cholangitis. This study aims at identifying differentially transcribed genes that govern liver pathology during this disease. Methods: Hepatic gene transcription was measured in 3, 6, 9 and 20 week old abcb4 (-/-) mice (FVB.129P2-abcb4tm1Bor/J) using cDNA microarrays; FVB/NJ abcb4 (+/+) mice serving as controls. Altered gene transcriptions were verified by real-time polymerase chain reaction. Attention focused on genes coding for chemokines and cytokines of potential pathogenic importance and on matrix housekeeping genes, growth factors and genes regulating wound healing, epithelial morphogenesis and tissue development. Disease phenotype was characterized by histopathology scoring. Results: Transcription of serpina3 genes showed early downregulation. Genes exhibiting upregulated transcription included: Cxcl10, Ccl2, Ccl20, Ctgf, Elf3, Lgals3, Mmp12, Mmp15, Spp1, Loxl2, Pdgfa, Pdgfrb, Sparc, Tgfbi, Tgfbr2. Conclusions: During early phases of chronic cholangitis in abcb4 (-/-) mice, hepatic downregulation of serpina3 genes and enhanced transcription of genes sustaining inflammatory processes contribute to fashioning the portal tract pathology. Later, enhanced transcription of genes governing tissue repair consolidate the portal tract pathology. Experiment Overall Design: A time-series where 5 male mice were sacrificed at time-points 3,6,9 and 20 weeks, both sick knockouts and healthy controls. Including one dye-swap there were a total of 6 arrays at each time-point.

Project description:Background & Aims: Ursodeoxycholic acid (UDCA) attenuates chemical and colitis-induced colon carcinogenesis in animal models. We investigated its mechanism of action on normal intestinal cells, in which carcinogenesis- or inflammation-related alterations do not interfere with the result. Methods: Alterations of gene expression were identified in Affymetrix arrays in isolated colon epithelium of mice fed with a diet containing 0.4% UDCA and were confirmed in the normal rat intestinal cell line IEC-6 by RT-PCR. The effect of the insulin receptor substrate 1 (Irs-1) expression and of ERK phosphorylation on proliferation was investigated in vitro by flow cytometry, western blotting, siRNA-mediated gene suppression or by pharmacological inhibition of the kinase activity. The ERK1-effect on Irs-1 transcription was tested in a reporter system. Results: UDCA-treatment in vivo suppressed potential pro-proliferatory genes including Irs-1 and reduced cell proliferation by more than 30%. In vitro it neutralised the proliferatory signals of IGF-1 and EGF and slowed down the cell cycle. Irs-1 transcription was suppressed due to high ERK1 activation. Both Irs-1 suppression and the persistent high ERK activation inhibited proliferation. Conversely, the decrease of phosphorylation of ERK1 (but not ERK2) or of its expression partially abrogated the inhibitory effects of UDCA. Conclusions: UDCA inhibits proliferation of intestinal epithelial cells by acting upon IGF-1 and EGF pathways and targeting ERK1 and, consequently, Irs-1. The inhibition of these pathways adds a new dimension to the physiological and therapeutic action of UDCA and, since both pathways are activated in inflammation and cancer, suggests new applications of UDCA in chemoprevention and chemotherapy. Six normal mice were used for isolation of control RNA and six mice were used for isolation of RNA after UDCA treatment. RNAs of two animals were pooled i.e. there were six treated samples, named T1+2;T3+4,T5+6 and six nontreated samples named N1+2;N3+4 and N5+6.

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Gene expression profiles of sclerosing cholangitis activity in mice

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