title: Impaired interferon signaling in chronic hepatitis C patients with advanced fibrosis via the transforming growth factor beta signaling pathway.
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).
  
  
  CONCLUSIONS
  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.
authors: Department of Gastroenterology, Kanazawa University Graduate School of Medicine, Kanazawa, Japan; Department of Advanced Medical Technology, Kanazawa University Graduate School of Health Medicine, Kanazawa, Japan.
authors: Takayoshi
authors: T
authors: Shirasaki
authors: Masao
authors: M
authors: Honda
authors: Tetsuro
authors: T
authors: Shimakami
authors: Kazuhisa
authors: K
authors: Murai
authors: Takayuki
authors: T
authors: Shiomoto
authors: Hikari
authors: H
authors: Okada
authors: Riuta
authors: R
authors: Takabatake
authors: Akihiro
authors: A
authors: Tokumaru
authors: Yoshio
authors: Y
authors: Sakai
authors: Taro
authors: T
authors: Yamashita
authors: Stanley M
authors: SM
authors: Lemon
authors: Seishi
authors: S
authors: Murakami
authors: Shuichi
authors: S
authors: Kaneko
mesh_terms: D000328:Adult; D000368:Aged; D000596:Amino Acids; D000818:Animals; D000998:Antiviral Agents / Q000627:therapeutic use; D045744:Cell Line, Tumor; D019587:Dietary Supplements; D004359:Drug Therapy, Combination; D005260:Female; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors / Q000378:metabolism; D005786:Gene Expression Regulation; D019698:Hepatitis C, Chronic / Q000150:complications / Q000188:drug therapy / Q000378:metabolism*; D006801:Humans; D007372:Interferons / Q000378:metabolism*; D007378:Interleukins / Q000235:genetics; D008099:Liver / Q000378:metabolism; D008103:Liver Cirrhosis / Q000378:metabolism* / Q000821:virology; D008297:Male; D000076222:Mechanistic Target of Rapamycin Complex 1; D051379:Mice; D008875:Middle Aged; D046912:Multiprotein Complexes / Q000378:metabolism; D009752:Nutritional Status; D016755:Proto-Oncogene Proteins c-jun / Q000378:metabolism; D012254:Ribavirin / Q000627:therapeutic use; D000071223:Suppressor of Cytokine Signaling 3 Protein; D050826:Suppressor of Cytokine Signaling Proteins / Q000378:metabolism; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000378:metabolism*; D000095022:Interferon Lambda
chemical_list: D000596:Amino Acids; D000998:Antiviral Agents; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors; D007372:Interferons; D007378:Interleukins; D000076222:Mechanistic Target of Rapamycin Complex 1; D046912:Multiprotein Complexes; D016755:Proto-Oncogene Proteins c-jun; D012254:Ribavirin; D000071223:Suppressor of Cytokine Signaling 3 Protein; D050826:Suppressor of Cytokine Signaling Proteins; D058570:TOR Serine-Threonine Kinases; D016212:Transforming Growth Factor beta; C499517:FOXO3 protein, human; C000624353:interferon-lambda, human; D000095022:Interferon Lambda; C106644:SOCS3 protein, human