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The role of Ifng in alterations in liver gene expression in a mouse model of fulminant autoimmune hepatitis.

ABSTRACT: BALB/c mice with a homozygous deficiency in the Tgfb1 gene are a model of fulminant autoimmune hepatitis (AIH), spontaneously and rapidly developing Th1-mediated IFN-gamma-dependent necroinflammatory liver disease. We sought to understand the molecular basis for fulminant Th1 liver disease and the specific role of the Ifng gene.Global gene expression in livers from BALB/c Tgfb1(-/-) mice with and without an intact Ifng gene was assessed by microarray analysis. Expression patterns were confirmed by quantitative reverse transcriptase-polymerase chain reaction. Gene ontology clustering analysis was performed to identify altered pathways. The contributions of Ifng to altered expression pathways were quantified.Over 100 genes were strongly (>10-fold) upregulated, most encoding proteins involved in immune function/response. Chemokines were the most prominently upregulated group, with eight chemokine genes upregulated >10-fold. Ifng was necessary for the upregulation of CXC chemokines gene, but not of CC chemokine genes. By quantitative analysis, Ifng's role in liver gene upregulation varied greatly among overexpressed genes.Gene expression changes indicate a particularly important and heretofore unappreciated role for chemokines in fulminant AIH. Ifng has an important role in expression of some but not all genes. Ifng is dichotomous in the regulation of distinct chemokine subfamilies: specifically, Ifng is critical for overexpression of specific CXCL genes but dispensable for overexpression of specific CCL genes. These results provide a clearer understanding of the role of Ifng in the molecular basis of necroinflammatory liver disease.

SUBMITTER: Milks MW

PROVIDER: S-EPMC3038248 | biostudies-literature | 2009 Oct

REPOSITORIES: biostudies-literature

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The role of Ifng in alterations in liver gene expression in a mouse model of fulminant autoimmune hepatitis.

Milks Michael W MW Cripps James G JG Lin Heping H Wang Jing J Robinson Richard T RT Sargent Jennifer L JL Whitfield Michael L ML Gorham James D JD

Liver international : official journal of the International Association for the Study of the Liver 20090416 9

<h4>Background/aims</h4>BALB/c mice with a homozygous deficiency in the Tgfb1 gene are a model of fulminant autoimmune hepatitis (AIH), spontaneously and rapidly developing Th1-mediated IFN-gamma-dependent necroinflammatory liver disease. We sought to understand the molecular basis for fulminant Th1 liver disease and the specific role of the Ifng gene.<h4>Methods</h4>Global gene expression in livers from BALB/c Tgfb1(-/-) mice with and without an intact Ifng gene was assessed by microarray analy ...[more]

PMID: 19490417

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Project description:AimTo study host gene expression and number of immune cells in liver tissues from patients with fulminant hepatitis E (FH-E).MethodsMicroarray-based expression profiling was done using Illumina Human WG-6_v3_BeadChip arrays on post-mortem liver tissue from 5 patients with FH-E, and compared with similar tissue from 6 patients with fulminant hepatitis B (FH-B; disease controls) and normal liver tissue from 6 persons. Differential expression was defined as ≥ 2.0-fold change with Benjamini-Hochberg false discovery rate below 0.05 using t-test in liver tissue from FH-B and FH-E, than healthy liver tissue. For some genes that showed differential expression in FH-E, microarray data were validated using quantitative reverse transcription PCR. Differentially expressed gene lists were then subjected to "Gene Ontology" analysis for biological processes, and pathway analysis using BioCarta database on the DAVID server. In addition, tissue sections were stained for CD4(+), CD8(+) and CD56(+) cells using indirect immunohistochemistry; cells staining positive for each of these markers were counted and compared between groups.ResultsCompared to normal livers, those from patients with FH-E and FH-B showed differential expression of 3377 entities (up-regulated 1703, downregulated 1674) and 2572 entities (up 1164, down 1408), respectively. This included 2142 (up 896, down 1246) entities that were common between the two sets; most of these belonged to metabolic, hemostatic and complement pathways, which are active in normal livers. Gene expression data from livers of patients with FH-E but not those of FH-B showed activation of several immune response pathways, particularly those involving cytotoxic T cells. The fold-change values of mRNA for selected genes in livers from FH-E than in normal liver tissue determined using quantitative reverse transcription PCR showed excellent concordance with microarray analysis. At immunohistochemistry, CD8(+) T cells showed an increase in liver biopsies from both FH-E [median 53.4 per arbitrary unit area (range 31.2-99.9)] and FH-B [median 49.3 (19.3-51.0); P = 0.005] compared to control liver tissue [median 6.9 (3.1-14.9)].ConclusionFH-E patients show CD8(+) T cell infiltration and increased gene expression of cytotoxic T cell pathways in liver, suggesting a possible pathogenetic role for these cells.

Project description:BackgroundThe prevalence of autoimmune hepatitis (AIH) is increasing, and its early clinical diagnosis is difficult. The pathogenesis of AIH remains unclear, and AIH-related studies are largely limited because of lack of suitable mouse models.MethodsTo obtain a good tool for research on AIH, we first established an improved immune-mediated mouse model that can mimic the pathological process of AIH as in the human body, through repeated injections of human cytochrome P450 2D6 (CYP2D6) plasmid. Next, a proteomic analysis based on isobaric tag (IBT) technology was performed to detect the differentially expressed proteins (DEPs), and related biological functions and pathways in the plasma of AIH and normal mice. Finally, we performed enzyme-linked immunosorbent assay (ELISA) to further confirm the most abundant DEP in the plasma of patients with AIH.ResultsAutoantibodies and the characteristic pathology of AIH were observed in our mouse model. Inflammatory infiltration also increased in the livers of AIH mice over time and plateaued by day 42 post the first injection. Chronic hepatitis was most severe on day 35 with the development of fibrosis as well, and the plasma of AIH mice were collected for proteomic analysis. A total of 176 DEPs were found in this experiment, of which 148 DEPs were up-regulated and 28 DEPs were down-regulated. Thirty significant Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways (P < 0.05) were detected. Arginine biosynthesis was found to be the most significant pathway involved in the AIH process. During the Gene Ontology (GO) analysis, most DEPs were found to be involved in the binding, cellular, and metabolic processes. Using ELISA, the most overexpressed DEP, serum amyloid A 1 (SAA1), was confirmed to be increased specifically in the plasma of patients with AIH compared to other chronic hepatitis. Different plasma levels of SAA1 were also found related to different grades of inflammation and stages of fibrosis in the liver of patients with AIH.ConclusionsOur study is the first to describe the proteomics analysis of a true sense of AIH mouse model, which is beneficial for a better understanding of AIH pathogenesis and identifying potential biomarkers for its clinical diagnosis.

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The role of Ifng in alterations in liver gene expression in a mouse model of fulminant autoimmune hepatitis.

Publications

The role of Ifng in alterations in liver gene expression in a mouse model of fulminant autoimmune hepatitis.

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