title: Regulation of CYP27B1 and CYP24A1 hydroxylases limits cell-autonomous activation of vitamin D in dendritic cells.
abstract: The active vitamin D metabolite 1α,25-dihydroxyvitamin D (1,25[OH]₂ D) potently inhibits DC priming of T-cell activation, suggesting that it mediates a homeostatic role in this context. Therefore, careful regulation of 1,25[OH]₂ D levels is necessary to avoid inappropriate inhibition of T-cell activation. Cell-autonomous control of vitamin D activity can be modulated by the action of the vitamin D-activating and -inactivating hydroxylases, CYP27B1, and CYP24A1, respectively. We show that in comparison to macrophages, human monocyte-derived DCs exhibit significantly less activation of 25-dihydroxyvitamin D to 1,25[OH]₂ D, and that DCs predominantly express a truncated CYP27B1 transcript that may contribute to the deficiency in activation of vitamin D. Furthermore, in response to stimulation with 1,25[OH]₂ D, upregulation of the inactivating enzyme CYP24A1 curtailed the functional effects of vitamin D in DCs, but not macrophages. Production of 1,25[OH]₂ D by macrophages was adequate to induce expression of vitamin D-responsive genes by DCs, inhibit DC maturation in response to innate immune stimulation and DC-dependent T-cell responses. Our data suggest that in comparison to macrophages, differential regulation of hydroxylases limits autocrine vitamin D activity in DCs, and that paracrine activation of vitamin D exerts a more potent mechanism for homeostatic control of DC function.
authors.affiliation: Division of Infection and Immunity, University College London, London, UK.
authors.forename: Rhiannon
authors.initials: R
authors.lastname: Kundu
authors.forename: Benjamin M
authors.initials: BM
authors.lastname: Chain
authors.forename: Anna K
authors.initials: AK
authors.lastname: Coussens
authors.forename: Bernard
authors.initials: B
authors.lastname: Khoo
authors.forename: Mahdad
authors.initials: M
authors.lastname: Noursadeghi
mesh_terms: D015090:25-Hydroxyvitamin D3 1-alpha-Hydroxylase / Q000276:immunology*; D002117:Calcitriol / Q000276:immunology*; D003713:Dendritic Cells / Q000166:cytology / Q000276:immunology*; D005260:Female; D006706:Homeostasis / Q000502:physiology; D006801:Humans; D008213:Lymphocyte Activation / Q000502:physiology*; D008264:Macrophages / Q000166:cytology / Q000276:immunology; D008297:Male; D009000:Monocytes / Q000166:cytology / Q000276:immunology; D013250:Steroid Hydroxylases / Q000276:immunology*; D013601:T-Lymphocytes / Q000166:cytology / Q000276:immunology*; D065668:Vitamin D3 24-Hydroxylase
chemical_list: D013250:Steroid Hydroxylases; C585549:CYP24A1 protein, human; D065668:Vitamin D3 24-Hydroxylase; D015090:25-Hydroxyvitamin D3 1-alpha-Hydroxylase; D002117:Calcitriol
keywords: CYP24A1; CYP27B1; DCs; Macrophages; Vitamin D