The role of vitamin D in the pathogenesis and treatment of chronic hepatitis C virus infection

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Recent clinical evidence suggests a role for vitamin D in the individual responsiveness to interferon-alfa (IFN-alfa)-based therapy of patients with chronic hepatitis C. By searching for the underlying mechanisms, we have identified the inactive vitamin D receptor (VDR) as a novel suppressor of IFN-alfa-induced Jak-STAT signaling in human hepatoma cell lines. The inhibitory impact of VDR was based on a constitutive interaction between the inactive VDR and Stat1, a key molecule in IFN-signal transduction, which was released after stimulation with calcitriol (the bioactive form of vitamin D) and IFN-alfa. As a consequence, calcitriol enhanced the effect of IFN-alfa against hepatitis C virus (HCV) replication in vitro. Implications of this newly identified receptor crosstalk between VDR and IFN-alfa-induced Jak-STAT signaling shall be investigated comprehensively within the here proposed research project. In detail, the impact of calcitriol / the VDR on type II- and III-IFN signaling (IFN-gamma and IFN-lambda) shall be investigated, including a respective in vitro analysis of the possible therapeutic potency of clinical available calcitriol analogues. In addition, the impact of calcitriol / the VDR on IFN signaling in macrophages shall be determined, including an analysis of IFN-dependent antiviral effector functions of macrophages. Finally, a comprehensive transcriptome analysis shall be performed with regard to the influence of the VDR-Stat1 interaction on global gene expression profiles, including potential implications for hepato-carcinogenesis. The results of these analyses may lead to the evaluation of calcitriol and its analogues in IFN-based therapies of various diseases.