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Aberrant TGF-?1 signaling contributes to the development of primary biliary cirrhosis in murine model.

ABSTRACT: To investigate whether transforming growth factor-?1 (TGF-?1) signaling pathway is involved in the pathogenesis of primary biliary cirrhosis (PBC).A murine model of PBC was developed by injection of polyinosinic polycytidylic acids (poly?I: C) in C57BL/6 mice, and the liver expressions of TGF ?1, TGF-? receptor?I?(T?RI), TGF-? receptor II (T?RII), p-Smad2/3, monoclonal ?-smooth muscle actin antibody (?-SMA) and ?1 (I) collagen in the mouse model and control mice were evaluated by immunohistochemistry, immunoblotting and real-time polymerase chain reaction (RT-PCR). Lymphocyte subsets in liver were analyzed using flow cytometry.The mouse model had several key phenotypic features of human PBC, including elevated levels of alkaline phosphatase, antimitochondrial antibodies, portal bile ducts inflammation, and progressive collagen deposition. Compared with control mice, protein and mRNA levels of TGF ?1, T?RI, T?RII, p-Smad2/3, ?-SMA and ?1 (I) collagen in liver (1.7 ± 0.4 vs 8.9 ± 1.8, 0.8 ± 0.2 vs 5.1 ± 1.5, 0.6 ± 0.01 vs 5.1 ± 0.1, 0.6 ± 0.3 vs 2.0 ± 0.3, 0.9 ± 0.4 vs 3.4 ± 0.6, 0.8 ± 0.4 vs 1.7 ± 0.3, 1.1 ± 1.2 vs 11.8 ± 0.6, P < 0.05), and the total number and percentage of CD4? CD25? FOXP3? and CD8? lymphocytes (0.01 ± 0.001 vs 0.004 ± 0.00, 0.12 ± 0.04 vs 0.52 ± 0.23, P < 0.01) were higher in the mouse model.TGF?1 might play a dual role in the development of PBC: it suppresses inflammatory response but operates to enhance fibrogenesis. The aberrant activity of TGF-?1 signaling contributes to the development of PBC.

SUBMITTER: Liu B

PROVIDER: S-EPMC3792337 | biostudies-literature | 2013 Sep

REPOSITORIES: biostudies-literature

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Aberrant TGF-β1 signaling contributes to the development of primary biliary cirrhosis in murine model.

Liu Bin B Zhang Xuan X Zhang Feng-Chun FC Zong Jin-Bao JB Zhang Wen W Zhao Yan Y

World journal of gastroenterology 20130901 35

<h4>Aim</h4>To investigate whether transforming growth factor-β1 (TGF-β1) signaling pathway is involved in the pathogenesis of primary biliary cirrhosis (PBC).<h4>Methods</h4>A murine model of PBC was developed by injection of polyinosinic polycytidylic acids (poly I: C) in C57BL/6 mice, and the liver expressions of TGF β1, TGF-β receptor I (TβRI), TGF-β receptor II (TβRII), p-Smad2/3, monoclonal α-smooth muscle actin antibody (α-SMA) and α1 (I) collagen in the mouse model and control mice were ...[more]

PMID: 24124327

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Project description:Primary biliary cirrhosis (PBC) is an immune-mediated chronic cholestatic liver disease with a slowly progressive course. Without treatment, most patients eventually develop fibrosis and cirrhosis of the liver and may need liver transplantation in the late stage of disease. PBC primarily affects women (female preponderance 9-10:1) with a prevalence of up to 1 in 1,000 women over 40 years of age. Common symptoms of the disease are fatigue and pruritus, but most patients are asymptomatic at first presentation. The diagnosis is based on sustained elevation of serum markers of cholestasis, i.e., alkaline phosphatase and gamma-glutamyl transferase, and the presence of serum antimitochondrial antibodies directed against the E2 subunit of the pyruvate dehydrogenase complex. Histologically, PBC is characterized by florid bile duct lesions with damage to biliary epithelial cells, an often dense portal inflammatory infiltrate and progressive loss of small intrahepatic bile ducts. Although the insight into pathogenetic aspects of PBC has grown enormously during the recent decade and numerous genetic, environmental, and infectious factors have been disclosed which may contribute to the development of PBC, the precise pathogenesis remains enigmatic. Ursodeoxycholic acid (UDCA) is currently the only FDA-approved medical treatment for PBC. When administered at adequate doses of 13-15 mg/kg/day, up to two out of three patients with PBC may have a normal life expectancy without additional therapeutic measures. The mode of action of UDCA is still under discussion, but stimulation of impaired hepatocellular and cholangiocellular secretion, detoxification of bile, and antiapoptotic effects may represent key mechanisms. One out of three patients does not adequately respond to UDCA therapy and may need additional medical therapy and/or liver transplantation. This review summarizes current knowledge on the clinical, diagnostic, pathogenetic, and therapeutic aspects of PBC.

Dataset Information

Aberrant TGF-?1 signaling contributes to the development of primary biliary cirrhosis in murine model.

Publications

Aberrant TGF-β1 signaling contributes to the development of primary biliary cirrhosis in murine model.

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