Original Article
Copyright ©2013 Baishideng Publishing Group Co., Limited. All rights reserved.
World J Gastroenterol. Sep 21, 2013; 19(35): 5828-5836
Published online Sep 21, 2013. doi: 10.3748/wjg.v19.i35.5828
Aberrant TGF-β1 signaling contributes to the development of primary biliary cirrhosis in murine model
Bin Liu, Xuan Zhang, Feng-Chun Zhang, Jin-Bao Zong, Wen Zhang, Yan Zhao
Bin Liu, Jin-Bao Zong, Department of Rheumatology, the Affiliated Hospital of Qingdao University Medical College, Qingdao 266003, Shandong Province, China
Bin Liu, Xuan Zhang, Feng-Chun Zhang, Wen Zhang, Yan Zhao, Department of Rheumatology, Peking Union Medical College Hospital, Chinese Academy of Medical Science, Beijing 100730, China
Author contributions: Liu B and Zhang X contributed equally to this work; Liu B performed the majority of experiments; Zhang X and Zhang FC designed the study and drafted the manuscript; Zong JB provided analytical tools and revised the manuscript; Zhang W and Zhao Y carried out the data acquisition and analysis; all authors have read and approved the final manuscript.
Supported by Grants from National Key Technology R and D Program in the 11th Five year Plan of China, No. 2008BAI59B03; grants from Emphasis Item Clinical Speciality, Ministry of Health of The People’s Republic of China, 2005
Correspondence to: Feng-Chun Zhang, MD, Department of Rheumatology, Peking Union Medical College Hospital, Chinese Academy of Medical Science, 1 Shuaifuyuan, Dongcheng District, Beijing 100730, China. zhangfccra@yahoo.com.cn
Telephone: +86-10-65295005 Fax: +86-10-65295005
Received: May 1, 2013
Revised: June 24, 2013
Accepted: July 9, 2013
Published online: September 21, 2013
Abstract

AIM: To investigate whether transforming growth factor-β1 (TGF-β1) signaling pathway is involved in the pathogenesis of primary biliary cirrhosis (PBC).

METHODS: 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 evaluated by immunohistochemistry, immunoblotting and real-time polymerase chain reaction (RT-PCR). Lymphocyte subsets in liver were analyzed using flow cytometry.

RESULTS: 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 β1, TβRI, TβRII, p-Smad2/3, α-SMA and α1 (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.

CONCLUSION: TGFβ1 might play a dual role in the development of PBC: it suppresses inflammatory response but operates to enhance fibrogenesis. The aberrant activity of TGF-β1 signaling contributes to the development of PBC.

Keywords: Primary biliary cirrhosis, Transforming growth factor-β1, Regulatory T cell, Liver

Core tip: Primary biliary cirrhosis (PBC) is an autoimmune liver disease. Recent studies suggest that transforming growth factor-β1 (TGF-β1) signaling pathway might play an important role in the pathogenesis of PBC. However, whether TGF-β1 signaling pathway is involved in the development of PBC is still unknown. The studies have provided new data of TGF-β1 signaling pathway involving the pathogenesis of PBC, which will pose significant impact on our understanding of the pathogeneses of PBC. TGF-β1 signaling pathway is a potential target for PBC treatment.