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.
Hepatol Res. 2011 Apr;41(4):364-74. doi: 10.1111/j.1872-034X.2011.00777.x. Epub 2011 Feb 23.
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.
The effects of SOCS-1 and SOCS-3 on hepcidin production were investigated using a complete genome, HCV replicon system.
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.
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.
铁调素是调节全身铁代谢的关键调节剂，其表达受丙型肝炎病毒（HCV）感染的调节。细胞因子信号转导抑制因子 1（SOCS-1）和 SOCS-3 作为 Jak/信号转导和转录激活因子信号通路的负调节剂。在这项研究中，我们研究了 HCV 感染如何调节 SOCS-1 和 SOCS-3 的产生，以及这些 SOCS 蛋白如何影响铁调素的产生。
使用完整的 HCV 基因组、HCV 复制子系统研究 SOCS-1 和 SOCS-3 对铁调素产生的影响。
出乎意料的是，复制子细胞中铁调素（HAMP）mRNA 和生物活性铁调素蛋白铁调素-25 的基础表达水平明显升高。无论 HCV 感染如何，白细胞介素-6（IL-6）刺激后 STAT3 均被激活，但复制子细胞中的激活程度大于治愈细胞。SOCS-3 蛋白的基础表达增强，但 SOCS-1 蛋白的基础表达降低。SOCS-3 的表达在受到 IL-6 刺激时显著增加，但 SOCS-1 不受 IL-6 诱导。有趣的是，SOCS-1 和 SOCS-3 基因表达的沉默增强了 STAT3 的激活和 HAMP 基因的表达。此外，SOCS-1 蛋白的过表达强烈抑制了 STAT3 的激活和 HAMP 基因的表达。
这项体外研究表明，HCV 感染增强了 SOCS-3 的表达，但降低了 SOCS-1 的表达。IL-6 诱导的铁调素上调受 SOCS-1 和 SOCS-3 的负调控。HCV 感染肝细胞中 SOCS1 和 SOCS3 的调节至少部分解释了 CH-C 中铁调素相对缺乏的原因。
