Impaired interferon signaling in chronic hepatitis C patients with advanced fibrosis via the transforming growth factor beta signaling pathway. Issue 5 (2nd October 2014)

• Record Type: Journal Article
• Authors: Shirasaki, Takayoshi; Honda, Masao; Shimakami, Tetsuro; Murai, Kazuhisa; Shiomoto, Takayuki; Okada, Hikari; Takabatake, Riuta; Tokumaru, Akihiro; Sakai, Yoshio; Yamashita, Taro; Lemon, Stanley M.; Murakami, Seishi; Kaneko, Shuichi
• Is Part Of: Hepatology. Volume 60:Issue 5(2014:Nov.)
• Page Start: 1519
• Page End: 1530
• Publication Date: 2014-10-02
• Subjects: Heart -- Diseases -- Nursing -- Periodicals; Lungs -- Diseases -- Nursing -- Periodicals; Intensive care nursing -- Periodicals; Foie -- Maladies -- Périodiques; 616.362
• DOI: 10.1002/hep.27277
• Languages: English
• ISSNs: 0270-9139

Abstract

<abstract abstract-type="main"> <title> <x xml:space="preserve">Abstract</x> </title> <p>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). <italic>Conclusion</italic>: 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. (H<sc>epatology</sc> 2014;60:1519–1530)</p> </abstract>