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

Abstract

BackgroundVitamin 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).MethodsHBV 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.ResultsCalcitriol 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.ConclusionsThese 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.Electronic supplementary materialThe online version of this article (10.1186/s10020-018-0055-0) contains supplementary material, which is available to authorized users.

The interplay between vitamin D and viral infections

“…The immunomodulatory role of vitamin D in viral infections is more complex and appears to vary based on the nature of pathogen and the type of immune function that is primarily responsible for disease resolution . In addition, the anti‐viral effects of vitamin D appears to be transient, ranging from differentially regulated viral immune responses to regulation of viral pathogenesis either directly or indirectly (Figure ).…”

Controversial Effects of Vitamin D and Related Genes on Viral Infections, Pathogenesis, and Treatment Outcomes

“…In turn, reduced VD levels were associated with the clinical progression of liver cirrhosis and adverse clinical outcomes [117]. In line with this clinical evidence, the downregulation of VDR expression in HBV-transfected cells caused an increase in HBV transcription and translation [118]. Effective antiviral therapy, in contrast, restored VD to normal levels in HBV patients [119].…”

Serum vitamin D and vitamin-D-binding protein levels in children with chronic hepatitis B

“…Some investigations have indicated that serum 25(OH)D level is negatively correlated with HBV load, and low 25(OH)D level is associated with HBV genotype B, HBsAg, and HBeAg[ 11 , 14 ]. Other studies have shown inconsistent results[ 8 , 10 , 12 ]. In the present study, 25(OH)D was not correlated with HBV DNA in patients with CHB, and serum levels of 25(OH)D did not differ significantly between patients with or without HBeAg, patients with HBV genotype B or C, patients with or without HBsAg, and patients with or without detectable HBV DNA.…”

“…Combination of the active form of vitamin D and vitamin D receptor (VDR) may inhibit the proliferation of Th1 cells and the release of cytokines and concurrently activate Th2 cells, thus regulating the immune response. However, HBV-transfected cells downregulate VDR expression, thereby preventing vitamin D from inhibiting transcription and translation of HBV in vitro , and HBV might use this mechanism to avoid the immune system[ 8 ]. Therefore, it is believed that vitamin D is closely linked to hepatitis B.…”