Vitamin D receptor and STAT3 cooperate to establish TET2-mediated tolerogenesis

The active form of vitamin D, 1,25-dihydroxyvitamin D3 (1,25(OH)2D3), induces stable tolerogenesis in dendritic cells (DCs). This process involves the vitamin D receptor (VDR), which translocates to the nucleus, binds its cognate genomic sites, and promotes epigenetic and transcriptional remodeling. In this study, we investigated the interplay between the VDR and other transcription factors to induce DNA methylation changes that might provide phenotypic stability to the tolerogenic phenotype of DCs. Our study reveals the occurrence of vitamin D-specific DNA demethylation and transcriptional activation at VDR binding sites associated with the acquisition of tolerogenesis. Tolerogenic properties in DCs are acquired together with activation of the IL6-JAK-STAT3 pathway. In fact, VDR directly binds the IL6 gene, and JAK2-mediated STAT3 phosphorylation is specific to vitamin D stimulation. VDR and the phosphorylated form of STAT3 interact with each other and with methylcytosine dioxygenase TET2 following vitamin D treatment. Most importantly, pharmacological inhibition of STAT3 phosphorylation reverts the vitamin-induced tolerogenic properties of DCs. Our results reveal an interplay between VDR and STAT3 leading to the DNA demethylation-dependent induction of tolerogenesis by vitamin D.