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


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.
Milks
Michael W
MW
Department of Pathology, Dartmouth Medical School, Dartmouth-Hitchcock Medical Center,One Medical Center Drive, Lebanon, NH 03756, USA.
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
D000818:Animals; D018925:Chemokines / Q000235:genetics; D004195:Disease Models, Animal; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D019693:Hepatitis, Autoimmune / Q000378:metabolism*; D007371:Interferon-gamma / Q000502:physiology*; D008099:Liver / Q000378:metabolism*; D051379:Mice; D008807:Mice, Inbred BALB C; D020133:Reverse Transcriptase Polymerase Chain Reaction; D053773:Transforming Growth Factor beta1 / Q000502:physiology
D018925:Chemokines; D053773:Transforming Growth Factor beta1; D007371:Interferon-gamma