Vitamin D receptor, STAT3, and TET2 cooperate to establish tolerogenesis

Cell Rep. 2022 Jan 18;38(3):110244. doi: 10.1016/j.celrep.2021.110244.

Abstract

The active form of vitamin D, 1,25-dihydroxyvitamin D3, induces a stable tolerogenic phenotype 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 report the occurrence of vitamin D-specific DNA demethylation and transcriptional activation at VDR binding sites associated with the acquisition of tolerogenesis in vitro. Differentiation to tolerogenic DCs associates with activation of the IL-6-JAK-STAT3 pathway. We show that JAK2-mediated STAT3 phosphorylation is specific to vitamin D stimulation. VDR and the phosphorylated form of STAT3 interact with each other to form a complex with methylcytosine dioxygenase TET2. Most importantly, pharmacological inhibition of JAK2 reverts vitamin D-induced tolerogenic properties of DCs. This interplay among VDR, STAT3, and TET2 opens up possibilities for modulating DC immunogenic properties in clinics.

Keywords: DNA methylation; IL-6-JAK-STAT; JAK2; STAT3; TET2; VDR; dendritic cells; tolerogenesis; vitamin D.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cells, Cultured
  • DNA-Binding Proteins / immunology*
  • DNA-Binding Proteins / metabolism
  • Dendritic Cells / immunology*
  • Dendritic Cells / metabolism
  • Dioxygenases / immunology*
  • Dioxygenases / metabolism
  • Humans
  • Immune Tolerance / immunology*
  • Receptors, Calcitriol / immunology*
  • Receptors, Calcitriol / metabolism
  • STAT3 Transcription Factor / immunology*
  • STAT3 Transcription Factor / metabolism

Substances

  • DNA-Binding Proteins
  • Receptors, Calcitriol
  • STAT3 Transcription Factor
  • STAT3 protein, human
  • VDR protein, human
  • Dioxygenases
  • TET2 protein, human