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TGF-β signaling is activated in patients with chronic HBV infection and repressed by SMAD7 overexpression after successful antiviral treatment

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Abstract

Objectives

Although animal studies demonstrated that Smad7 induction ameliorates TGF-β/SMAD-mediated fibrogenesis, its role in human hepatic diseases is rather obscure. Our study explored the activation status of TGF-β/activin pathway in patients with chronic liver diseases, and how it is affected by successful antiviral treatment in chronic HBV hepatitis (CHB).

Methods

Thirty-seven CHB patients (19 with active disease, 14 completely remitted on long-term antiviral treatment and 4 with relapse after treatment withdrawal), 18 patients with chronic HCV hepatitis, 12 with non-alcoholic fatty liver disease (NAFLD), and 3 controls were enrolled in the study. Liver mRNA levels of CTGF, all TGF-β/activin isoforms, their receptors and intracellular mediators (SMADs) were evaluated using qRT-PCR and were correlated with the grade of liver inflammation and fibrosis staging. The expression and localization of pSMAD2 and pSMAD3 were assessed by immunohistochemistry.

Results

TGF-β signalling is activated in CHB patients with active disease, while SMAD7 is up-regulated during the resolution of inflammation after successful treatment. SMAD7 overexpression was also observed in NAFLD patients exhibiting no or minimal fibrosis, despite the activation of TGF-β/activin signaling.

Conclusions

SMAD7 overexpression might represent a mechanism limiting TGF-β-mediated fibrogenesis in human hepatic diseases; therefore, SMAD7 induction likely represents a candidate for novel therapeutic approaches.

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Acknowledgments

The authors want to thank Dr S. Anastasiadis for collecting patients’ samples and Dr A. Stavropoulos for his excellent technical support.

This research has been co-financed by the ESF and Greek national funds through the Operational Program “Education and Lifelong Learning” of the NSRF–Research Funding Program: Heracleitus II. Investing in knowledge society through the European Social Fund, and was also granted by the Research Committee of Aristotle University of Thessaloniki. PS and EA were also supported by a grant (TGF-LUNG-CURE 3451) from the ARISTEIA II program which has been co-financed by the European Union (European Social Fund–ESF) and Greek national funds through the Operational Program “Education and Lifelong Learning” of the National Strategic Reference Framework (NSRF).

Authors’ contribution

Study concept and design: MS, AEG; acquisition of data: AN, EA, PH; analysis and interpretation of data: NA, GG, PH, MS; drafting of the manuscript: NA, GG, MS; critical revision of the manuscript for important intellectual content: GG, PS, PH, AEG; statistical analysis: AN, MS; obtained funding: NA, GG, TV, PS, MS; technical, or material support: GG, TV, KP; study supervision: MS.

Author information

Authors and Affiliations

  1. Department of Immunology and Histocompatibility, University of Thessaly, School of Health Sciences, Faculty of Medicine, Biopolis, 41500, Larissa, Greece

    Nikoletta Argentou, Anastasios E. Germenis & Matthaios Speletas

  2. First Department of Internal Medicine, AHEPA Hospital, Aristotle University of Thessaloniki, School of Medicine, 54636, Thessaloniki, Greece

    Georgios Germanidis

  3. Department of Pathology, AHEPA Hospital, Aristotle University of Thessaloniki, School of Medicine, Kyriakidi Str. 1, 54636, Thessaloniki, Greece

    Prodromos Hytiroglou

  4. Centre for Clinical, Experimental Surgery and Translational Research, Biomedical Research Foundation Academy of Athens, 11527, Athens, Greece

    Eirini Apostolou & Paschalis Sideras

  5. Third Department of Internal Medicine, Papageorgiou Hospital, Aristotle University of Thessaloniki, 56403, Thessaloniki, Greece

    Themistoklis Vassiliadis

  6. Department of Pathology, Hippokration Hospital, 54635, Thessaloniki, Greece

    Kalliopi Patsiaoura

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  1. Nikoletta Argentou
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Correspondence to Matthaios Speletas.

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Argentou, N., Germanidis, G., Hytiroglou, P. et al. TGF-β signaling is activated in patients with chronic HBV infection and repressed by SMAD7 overexpression after successful antiviral treatment. Inflamm. Res. 65, 355–365 (2016). https://doi.org/10.1007/s00011-016-0921-6

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  • DOI: https://doi.org/10.1007/s00011-016-0921-6

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