Identification of novel molecules and pathogenic pathways in primary biliary cirrhosis: cDNA array analysis of intrahepatic differential gene expression

Background-Primary biliary cirrhosis (PBC) is an autoimmune disease in whic h the pathogenesis of progressive liver injury is poorly understood. Aim-To provide novel insights into the pathogenesis of PBC related liver in jury using cDNA array analysis, which simultaneously examines expression of many genes. Methods-Utilising cDNA arrays of 874 genes, PBC was compared with primary s clerosing cholangitis (PSC) associated cirrhosis and non-diseased liver. Di fferential expression of 10 genes was confirmed by real time quantitative r everse transcriptase-polymerase chain reaction (RT-PCR). Results-Array analysis identified many differentially expressed genes that are important in inflammation, fibrosis, proliferation, signalling, apoptos is, and oxidative stress. PBC was associated with increased expression of b oth Th1 and Th2 type molecules of the immune response. Fibrosis related gen e expression featured upregulation of connective tissue growth factor and t ransforming growth factor beta3. Many more apoptosis associated molecules e xhibited increased expression, consistent with apoptosis being a more activ e and regulated process, in PSC associated cirrhosis than in PBC. Increased expression of many genes of the Wnt and notch pathways implicated these hi ghly conserved and linked pathways in PBC pathogenesis. The observed increa ses in expression of c-jun, c-myc, and c-fos related antigen I are consiste nt with increased Wnt pathway activity in PBC. Differential expression of f our components of the Wnt pathway, Wnt-5a, Wnt13, FRITZ, and beta-catenin, was confirmed by quantitative RT-PCR. Conclusion-Many genes implicated in intrahepatic inflammation, fibrosis, an d regeneration were upregulated in PBC cirrhosis. In particular, increased expression of a number of Drosophila homologues was seen in PBC.