Impaired interferon signaling in chronic hepatitis C patients with advanced fibrosis via the transforming growth factor beta signaling pathway

Authors

  • Takayoshi Shirasaki,

    1. Department of Gastroenterology, Kanazawa University Graduate School of Medicine, Kanazawa, Japan
    2. Department of Advanced Medical Technology, Kanazawa University Graduate School of Health Medicine, Kanazawa, Japan
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  • Masao Honda,

    Corresponding author
    1. Department of Gastroenterology, Kanazawa University Graduate School of Medicine, Kanazawa, Japan
    2. Department of Advanced Medical Technology, Kanazawa University Graduate School of Health Medicine, Kanazawa, Japan
    • Address reprint requests to: Masao Honda, M.D., Ph.D., Department of Gastroenterology, Graduate School of Medicine, Kanazawa University, Takara-Machi 13-1, Kanazawa 920-8641, Japan. E-mail: mhonda@m-kanazawa.jp; fax: +81-76-234-4250.

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  • Tetsuro Shimakami,

    1. Department of Gastroenterology, Kanazawa University Graduate School of Medicine, Kanazawa, Japan
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  • Kazuhisa Murai,

    1. Department of Gastroenterology, Kanazawa University Graduate School of Medicine, Kanazawa, Japan
    2. Department of Advanced Medical Technology, Kanazawa University Graduate School of Health Medicine, Kanazawa, Japan
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  • Takayuki Shiomoto,

    1. Department of Gastroenterology, Kanazawa University Graduate School of Medicine, Kanazawa, Japan
    2. Department of Advanced Medical Technology, Kanazawa University Graduate School of Health Medicine, Kanazawa, Japan
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  • Hikari Okada,

    1. Department of Gastroenterology, Kanazawa University Graduate School of Medicine, Kanazawa, Japan
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  • Riuta Takabatake,

    1. Department of Gastroenterology, Kanazawa University Graduate School of Medicine, Kanazawa, Japan
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  • Akihiro Tokumaru,

    1. Department of Gastroenterology, Kanazawa University Graduate School of Medicine, Kanazawa, Japan
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  • Yoshio Sakai,

    1. Department of Gastroenterology, Kanazawa University Graduate School of Medicine, Kanazawa, Japan
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  • Taro Yamashita,

    1. Department of Gastroenterology, Kanazawa University Graduate School of Medicine, Kanazawa, Japan
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  • Stanley M. Lemon,

    1. Division of Infectious Diseases, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
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  • Seishi Murakami,

    1. Department of Gastroenterology, Kanazawa University Graduate School of Medicine, Kanazawa, Japan
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  • Shuichi Kaneko

    1. Department of Gastroenterology, Kanazawa University Graduate School of Medicine, Kanazawa, Japan
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  • Potential conflict of interest: Nothing to report.

Abstract

Malnutrition in the advanced fibrosis stage of chronic hepatitis C (CH-C) impairs interferon (IFN) signaling by inhibiting mammalian target of rapamycin complex 1 (mTORC1) signaling. However, the effect of profibrotic signaling on IFN signaling is not known. Here, the effect of transforming growth factor (TGF)-β signaling on IFN signaling and hepatitis C virus (HCV) replication was examined in Huh-7.5 cells by evaluating the expression of forkhead box O3A (Foxo3a), suppressor of cytokine signaling 3 (Socs3), c-Jun, activating transcription factor 2, ras homolog enriched in brain, and mTORC1. The findings were confirmed in liver tissue samples obtained from 91 patients who received pegylated-IFN and ribavirin combination therapy. TGF-β signaling was significantly up-regulated in the advanced fibrosis stage of CH-C. A significant positive correlation was observed between the expression of TGF-β2 and mothers against decapentaplegic homolog 2 (Smad2), Smad2 and Foxo3a, and Foxo3a and Socs3 in the liver of CH-C patients. In Huh-7.5 cells, TGF-β1 activated the Foxo3a promoter through an AP1 binding site; the transcription factor c-Jun was involved in this activation. Foxo3a activated the Socs3 promoter and increased HCV replication. TGF-β1 also inhibited mTORC1 and IFN signaling. Interestingly, c-Jun and TGF-β signaling was up-regulated in treatment-resistant IL28B minor genotype patients (TG/GG at rs8099917), especially in the early fibrosis stage. Branched chain amino acids or a TGF-β receptor inhibitor canceled these effects and showed an additive effect on the anti-HCV activity of direct-acting antiviral drugs (DAAs). Conclusion: Blocking TGF-β signaling could potentiate the antiviral efficacy of IFN- and/ or DAA-based treatment regimens and would be useful for the treatment of difficult-to-cure CH-C patients. (Hepatology 2014;60:1519–1530)

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