Division of Gastroenterology and Hepatology, Vaud University Hospital Center, University of Lausanne, CH-1011 Lausanne, Switzerland; Department of Medicine 1, J.W. Goethe University Hospital, D-60590 Frankfurt, Germany; and
Division of Gastroenterology and Hepatology, Vaud University Hospital Center, University of Lausanne, CH-1011 Lausanne, Switzerland;
J Immunol. 2014 Jun 15;192(12):6037-44. doi: 10.4049/jimmunol.1302296. Epub 2014 May 12.
Recent clinical research suggests a role for vitamin D in the response to IFN-α-based therapy of chronic hepatitis C. Therefore, we aimed to explore the underlying mechanisms in vitro. Huh-7.5 cells harboring subgenomic hepatitis C virus (HCV) replicons or infected with cell culture-derived HCV were exposed to bioactive 1,25-dihydroxyvitamin D3 (calcitriol) with or without IFN-α. In these experiments, calcitriol alone had no effect on the HCV life cycle. However, calcitriol enhanced the inhibitory effect of IFN-α on HCV replication. This effect was based on a calcitriol-mediated increase of IFN-α-induced gene expression. Further mechanistic studies revealed a constitutive inhibitory interaction between the inactive vitamin D receptor (VDR) and Stat1, which was released upon stimulation with calcitriol and IFN-α. As a consequence, IFN-α-induced binding of phosphorylated Stat1 to its DNA target sequences was enhanced by calcitriol. Importantly, and in line with these observations, silencing of the VDR resulted in an enhanced hepatocellular response to IFN-α. Our findings identify the VDR as a novel suppressor of IFN-α-induced signaling through the Jak-STAT pathway.
最近的临床研究表明，维生素 D 在慢性丙型肝炎的 IFN-α 治疗反应中具有作用。因此，我们旨在体外探索其潜在机制。携带亚基因组丙型肝炎病毒（HCV）复制子的 Huh-7.5 细胞或感染细胞培养衍生的 HCV 的细胞暴露于生物活性 1,25-二羟维生素 D3（骨化三醇）和/或 IFN-α。在这些实验中，骨化三醇本身对 HCV 生命周期没有影响。然而，骨化三醇增强了 IFN-α对 HCV 复制的抑制作用。这种作用基于骨化三醇介导的 IFN-α诱导基因表达的增加。进一步的机制研究揭示了无活性维生素 D 受体（VDR）与 Stat1 之间的组成性抑制相互作用，这种相互作用在受到骨化三醇和 IFN-α刺激时被释放。因此，骨化三醇增强了 IFN-α诱导的磷酸化 Stat1 与 DNA 靶序列的结合。重要的是，与这些观察结果一致，VDR 的沉默导致对 IFN-α的肝细胞反应增强。我们的研究结果确定 VDR 是 Jak-STAT 通路中 IFN-α 诱导信号的新型抑制因子。
