The etiology of liver damage imparts cytokines transforming ... : Hepatology (original) (raw)

Liver Biology/Pathobiology

The etiology of liver damage imparts cytokines transforming growth factor β1 or interleukin-13 as driving forces in fibrogenesis#

Weng, Hong-Lei1,2*†; Liu, Yan1; Chen, Jia-Lin3; Huang, Tong4; Xu, Li-Jun5; Godoy, Patricio1; Hu, Jun-Hua1; Zhou, Cheng2; Stickel, Felix6; Marx, Alexander7; Bohle, Rainer M.8; Zimmer, Vincent9; Lammert, Frank9; Mueller, Sebastian10; Gigou, Michelle11; Samuel, Didier11; Mertens, Peter R.12; Singer, Manfred V.1; Seitz, Helmut K.10; Dooley, Steven1*†

1 Molecular Alcohol Research in Gastroenterology, Department of Medicine II, Heidelberg, Germany

2 Institute of Infectious Diseases, First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China

3 Department of Pathology, First Hospital of Jianxing, College of Jiaxing, Jiaxing, China

4 Department of Internal Medicine, Zhenhai Lianhua Hospital, Ningbo, China

5 Institute of Liver Diseases, Fuzhou Infectious Diseases Hospital, Fujian Medical University, Fuzhou, China

6 Institute of Clinical Pharmocology, University of Bern, Bern, Switzerland

7 Department of Pathology, Faculty of Medicine at Mannheim, Heidelberg, Germany

8 Institute of Pathology, University of Saarland, Homburg, Germany

9 Department of Internal Medicine II, University of Saarland, Homburg, Germany

10 Department of Medicine and Laboratory of Alcohol Research, Liver Diseases, and Nutrition, Salem Medical Center, University of Heidelberg, Heidelberg, Germany

11 Institut National de la Santé et de la Recherche Médicale, Villejuif, France

12 Department of Nephrology and Hypertension, Otto-von-Guericke-University Magdeburg, Magdeburg, Germany

* Molecular Alcohol Research in Gastroenterology, Department of Medicine II, Faculty of Medicine at Mannheim, University of Heidelberg, Germany, Theodor-Kutzer Ufer 1-3, 68167 Mannheim, Germany

Email:[email protected]

Received October 6, 2008; accepted February 18, 2009.

Published online 3 March 2009 in Wiley InterScience (www.interscience.wiley.com).

Grant sponsor: Returned Overseas Chinese Scholars, State Education Ministry; Grant Number: SRF for ROCS, SEM, J20050337491010-G50523; Grant sponsor: People's Republic of China; Grant sponsor: Else-Kröner Fresenius; Grant sponsor: Deutsche Forschungsgemeinschaft; Grant Number: DO373/6-1; Grant sponsor: BMBF “Hepatosys”; Grant Numbers: SFB 542 projects A11/C4/C12 TRR 57 P03; Grant sponsor: Dietmar Hopp Stiftung GmbH.

# Potential conflict of interest: Nothing to report.

† Fax: (49)-621-383-1467

Additional Supporting Information may be found in the online version of this article.

Abstract

It is unknown whether transforming growth factor β1 (TGF-β1) signaling uniformly participates in fibrogenic chronic liver diseases, irrespective of the underlying origin, or if other cytokines such as interleukin (IL)-13 share in fibrogenesis (e.g., due to regulatory effects on type I pro-collagen expression). TGF-β1 signaling events were scored in 396 liver tissue samples from patients with diverse chronic liver diseases, including hepatitis B virus (HBV), hepatitis C virus (HCV), Schistosoma japonicum infection, and steatosis/steatohepatitis. Phospho-Smad2 staining correlated significantly with fibrotic stage in patients with HBV infection (n = 112, P < 0.001) and steatosis/steatohepatitis (n = 120, _P_ < 0.01), but not in patients with HCV infection (n = 77, _P_ > 0.05). In tissue with HBx protein expression, phospho-Smad2 was detectable, suggesting a functional link between viral protein expression and TGF-β1 signaling. For IL-13, immunostaining correlated with fibrotic stage in patients with HCV infection and steatosis/steatohepatitis. IL-13 protein was more abundant in liver tissue lysates from three HCV patients compared with controls, as were IL-13 serum levels in 68 patients with chronic HCV infection compared with 20 healthy volunteers (72.87 ± 26.38 versus 45.41 ± 3.73, P < 0.001). Immunohistochemistry results suggest that IL-13–mediated liver fibrogenesis may take place in the absence of phospho–signal transducer and activator of transcription protein 6 signaling. In a subgroup of patients with advanced liver fibrosis (stage ≥3), neither TGF-β nor IL-13 signaling was detectable. Conclusion: Depending on the cause of liver damage, a predominance of TGF-β or IL-13 signaling is found. TGF-β1 predominance is detected in HBV-related liver fibrogenesis and IL-13 predominance in chronic HCV infection. In some instances, the underlying fibrogenic mediator remains enigmatic. (Hepatology 2009.)