title: Effect of suppressor of cytokine signaling on hepcidin production in hepatitis C virus replicon cells.
abstract: OBJECTIVE
  Hepcidin is a key regulator of systemic iron metabolism and its expression is modulated by hepatitis C virus (HCV) infection. Suppressor of cytokine signaling 1 (SOCS-1) and SOCS-3 act as negative regulators of the Jak/signal transducers and activators of transcription signaling pathway. In this study, we investigated how HCV infection modulates SOCS-1 and SOCS-3 production and how these SOCS proteins affect hepcidin production.
  
  
  METHODS
  The effects of SOCS-1 and SOCS-3 on hepcidin production were investigated using a complete genome, HCV replicon system.
  
  
  RESULTS
  Unexpectedly, basal expression levels of hepcidin (HAMP) mRNA and the bioactive form of hepcidin protein, hepcidin-25, were significantly higher in replicon cells. Regardless of HCV infection, STAT3 was activated in response to interleukin-6 (IL-6), but this activation was greater in replicon cells than in cured cells. Basal expression of the SOCS-3 protein was enhanced, but basal expression of SOCS-1 protein was reduced, in replicon cells. Expression of SOCS-3 increased dramatically in response to IL-6 stimulation but expression of SOCS-1 was not induced by IL-6. Interestingly, silencing of SOCS-1 and SOCS-3 gene expression enhanced STAT3 activation and HAMP gene expression. In addition, overexpression of SOCS-1 protein strongly suppressed STAT3 activation and HAMP gene expression.
  
  
  CONCLUSIONS
  This in vitro study shows that SOCS-3 expression was enhanced but SOCS-1 expression was reduced by HCV infection. The upregulation of hepcidin induced by IL-6 was found to be negatively regulated by SOCS-1 and SOCS-3. The modulation of SOCS1 and SOCS3 in HCV-infected hepatocytes may explain, at least in part, the relative shortage of hepcidin production in CH-C.
authors.affiliation: Department of Gastroenterology and Hepatology, Mie University Graduate school of Medicine Center for Physical and Mental Health, Mie University Graduate School of Medicine Department of Immunology, Mie University Graduate School of Medicine, Mie, Japan Klinik für Unfall-, Hand- und Wiederherstellungschirurgie, J.W. Goethe-Universität Frankfurt, Frankfurt am Main, Germany.
authors.forename: Hirohide
authors.initials: H
authors.lastname: Miyachi
authors.forename: Yoshinao
authors.initials: Y
authors.lastname: Kobayashi
authors.forename: Borna
authors.initials: B
authors.lastname: Relja
authors.forename: Naoki
authors.initials: N
authors.lastname: Fujita
authors.forename: Motoh
authors.initials: M
authors.lastname: Iwasa
authors.forename: Esteban Cesar
authors.initials: EC
authors.lastname: Gabazza
authors.forename: Yoshiyuki
authors.initials: Y
authors.lastname: Takei