Hepatitis B virus downregulates vitamin D receptor levels in hepatoma cell lines, thereby preventing vitamin D-dependent inhibition of viral transcription and production

Neta Gotlieb, Irena Tachlytski, Yelena Lapidot, Maya Sultan, Michal Safran, Ziv Ben-Ari

    Research output: Contribution to journalArticlepeer-review

    Abstract

    Background: Vitamin D is a key immune-modulator that plays a role in the innate and adaptive immune systems. Certain pathogens impair the immune defense by downregulating the vitamin D receptor (VDR) pathway. Low serum levels of vitamin D are associated with increased hepatitis B virus (HBV) replication. Our study aimed to assess the in-vitro relationship between HBV production and Vitamin D signaling pathway and to explore the associated mechanism(s). Methods: HBV transcription and replication was evaluated by qRT-PCR of the HBV-RNA and covalently closed circular DNA (cccDNA). Furthermore, we have transfected the 1.3 X HBV-Luc plasmid to the cells and measured the Luciferase activity using Luminometer. Vitamin D signaling pathway activation was evaluated by measuring the expression levels of VDR, CYP24A1, Tumor necrosis factor α (TNFα) and cathelicidin (CAMP) by qRT-PCR. All assays were performed on HepG2.2.15, HepG2, and HepAD38 cells treated with or without Vitamin D active metabolite: calcitriol. Results: Calcitriol did not suppress HBV transcription, cccDNA expression or HBV RNA levels in HepG2.2.15 cells. However, VDR transcript levels in HepG2.215 cells were significantly lower compared to HepG2 cells. Similar results were obtained in HepAD38 cell where VDR expression was down-regulated when HBV transcript level was up-regulated. In addition, calcitriol induced VDR-associated signaling, resulting in upregulation of CYP24A1, TNFα and CAMP expression level in HepG2 cells but not in the HepG2.2.15 cells. Conclusions: These findings indicate that VDR expression is downregulated in HBV-transfected cells, thereby preventing vitamin D from inhibiting transcription and translation of HBV in vitro. HBV might use this mechanism to avoid the immunological defense system by affecting both TNFα and CAMP signaling pathways.

    Original languageEnglish
    Article number53
    JournalMolecular Medicine
    Volume24
    Issue number1
    DOIs
    StatePublished - 16 Oct 2018

    Keywords

    • Downregulation
    • Hepatitis B virus (HBV)
    • Immune system
    • Vitamin D
    • Vitamin D receptor (VDR)

    Fingerprint

    Dive into the research topics of 'Hepatitis B virus downregulates vitamin D receptor levels in hepatoma cell lines, thereby preventing vitamin D-dependent inhibition of viral transcription and production'. Together they form a unique fingerprint.

    Cite this