Effect of suppressor of cytokine signaling on hepcidin production in hepatitis C virus replicon cells

• Published in: Hepatology research 2011-04, Vol.41 (4), p.364-374
• Main Authors: Miyachi, Hirohide, Kobayashi, Yoshinao, Relja, Borna, Fujita, Naoki, Iwasa, Motoh, Gabazza, Esteban Cesar, Takei, Yoshiyuki
• Format: Article
• Language: English
• Subjects: Gene expression; Genomes; Hepatitis C virus; Hepatocytes; Hepcidin; Infection; Interleukin 6; Iron; iron metabolism; Metabolism; replicon; Signal transduction; SOCS-1 protein; SOCS-3 protein; Stat3 protein; suppressor of cytokine signaling; Transcription
• ISSN: 1386-6346; 1872-034X
• DOI: 10.1111/j.1872-034X.2011.00777.x

Aim:  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.