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The role of Ifng in alterations in liver gene expression in a mouse model of fulminant autoimmune hepatitis
Author(s) -
Milks Michael W.,
Cripps James G.,
Lin Heping,
Wang Jing,
Robinson Richard T.,
Sargent Jennifer L.,
Whitfield Michael L.,
Gorham James D.
Publication year - 2009
Publication title -
liver international
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.873
H-Index - 110
eISSN - 1478-3231
pISSN - 1478-3223
DOI - 10.1111/j.1478-3231.2009.02028.x
Subject(s) - chemokine , biology , autoimmune hepatitis , downregulation and upregulation , microarray analysis techniques , gene expression , gene , immunology , regulation of gene expression , gene expression profiling , immune system , hepatitis , genetics
Background/Aims: 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‐γ‐dependent necroinflammatory liver disease. We sought to understand the molecular basis for fulminant Th1 liver disease and the specific role of the Ifng gene. Methods: 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. Results: 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. Conclusions: 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.