5-Aza-2′-deoxycytidine enhances the antimicrobial response of vitamin D receptor against Mycobacterium tuberculosis

Abstract

Objective: Epigenetic modification affects disease susceptibility. In this study, we analyzed the relationship between the methylation regulation of VDR by the DNA methyltransferase inhibitor, 5-aza-2′-deoxycytidine (AZA), and TB susceptibility, as well as the underlying mechanism of this relationship. Methods: real-time PCR was used to determine the mRNA expression changes of VDR gene under the BCG infection and AZA treatment. Additionally, immunoblot analysis was implemented to study the phosphorylation changes of AKT, GSK3β, ERK, p38 after the inhibition of the VDR and the application of AZA. Furthermore, the use of colony counting evaluated the effect of the VDR and AZA on BCG's viability in vitro. The BCG infected mouse model was constructed and used to analyze the effect of VDR methylation changes and the process of TB. Results: the BCG infection and the AZA treatment affected the expression of VDR gene in RAW 264.7 cells. The inhibition of VDR decreased the phosphorylation of AKT, while AZA treatment induced the expression of VDR. Both the inhibition of VDR and the application of AZA changed the quantity of live BCG in THP-1 cells. In the BCG infected mouse, the application of AZA reduced the TB susceptibility. Conclusions: our results suggested that the application of AZA promoted the expression of VDR and enhanced the antimicrobial response of VDR against Mtb.