Gene expression profile of the infective murine model for biliary atresia.
One hypothesis of the pathogenesis of biliary atresia (BA) is a virus-induced and immune-mediated injury to bile duct cells as mimicked in the rotavirus-induced murine model. This theory is supported by studies showing a predominant T helper cell response type 1-like phenotype of inflammation with increased interferon gamma-induced chemokines in the liver of humans and mice suffering from BA. Recent gene expression profiling studies using microarray analysis showed the induction of a proinflammatory state in human liver specimens with high analogies in extrahepatic biliary tissue of BA mice. The aim of the present study was a microarray analysis of gene expression in the liver of Balb/c mice, comparing infected mice that show the phenotype of BA versus infected mice without symptoms, thus trying to elucidate genes that are not related to the viral origin of this model, but to the specific pathogenesis of the clinical picture of BA. Fifteen mug of RNA, each of three BA-positive and three BA-negative mice, were pooled and comparatively hybridized to spotted cDNA microarrays containing 250 key genes with high relevance to immunological settings. We identified the 40 genes most differentially expressed in mice with and without BA. The majority of genes with higher expression in BA-positive mice encoded proinflammatory cytokines involved in the Th1 pathway, such as CCL2, CCL5, CCR5, CXCL10, CCL2, IL1F5 and in apoptosis, such as DDR3 and granzyme A and B. In this initial study of the molecular characterization of our RRV-induced BA mouse model system, we also found potential novel candidates important to BA etiology, such as growth hormone receptor and insulin-like growth factor. Of particular interest, very low expression of TIMD2 was observed in BA-positive mice. TIMD2 plays a critical role in the regulation of a Th2-type response through the inhibition of IFN gamma.
Leonhardt
Johannes
J
Department of Pediatric Surgery, Hannover Medical School, Carl-Neuberg-Strasse 1, 30625 Hannover, Germany. leonhardt.johannes@mh-hannover.de
Stanulla
Martin
M
von Wasielewski
Reinhard
R
Skokowa
Julia
J
Kübler
Joachim
J
Ure
Benno M
BM
Petersen
Claus
C
D000818:Animals; D001656:Biliary Atresia / Q000235:genetics* / Q000276:immunology* / Q000473:pathology / Q000821:virology; D015870:Gene Expression; D008099:Liver / Q000378:metabolism; D008565:Membrane Proteins / Q000235:genetics; D051379:Mice; D008807:Mice, Inbred BALB C; D020411:Oligonucleotide Array Sequence Analysis; D012400:Rotavirus Infections
D008565:Membrane Proteins; C442242:Timd2 protein, mouse