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Cell Rep. 2015 Feb 4. pii: S2211-1247(15)00026-1. doi: 10.1016/j.celrep.2015.01.013. [Epub ahead of print]

Vitamin D3 Induces Tolerance in Human Dendritic Cells by Activation of Intracellular Metabolic Pathways.

Author information

1
Laboratory of Clinical and Experimental Endocrinology, Department of Clinical and Experimental Medicine, KU Leuven, Leuven 3000, Belgium.
2
Laboratory of Angiogenesis and Neurovascular Link, Vesalius Research Center, VIB, Leuven 3000, Belgium; Laboratory of Angiogenesis and Neurovascular Link, Vesalius Research Center, VIB, Department of Oncology, KU Leuven, Leuven 3000, Belgium.
3
Department of Microbial and Molecular Systems, KU Leuven, Leuven 3000, Belgium.
4
Gene Expression Unit, Department of Cellular and Molecular Medicine, KU Leuven, Leuven 3000, Belgium.
5
Department of Microbial and Molecular Systems, KU Leuven, Leuven 3000, Belgium; Department of Plant Biotechnology and Bioinformatics, Ghent University, Ghent 9000, Belgium; Department of Information Technology, IMinds, Ghent University, Ghent 9000, Belgium.
6
Laboratory of Experimental Medicine, Free University of Brussels, Brussels 1050, Belgium.
7
Laboratory of Clinical and Experimental Endocrinology, Department of Clinical and Experimental Medicine, KU Leuven, Leuven 3000, Belgium. Electronic address: lut.overbergh@med.kuleuven.be.

Abstract

Metabolic switches in various immune cell subsets enforce phenotype and function. In the present study, we demonstrate that the active form of vitamin D, 1,25-dihydroxyvitamin D3 (1,25(OH)2D3), induces human monocyte-derived tolerogenic dendritic cells (DC) by metabolic reprogramming. Microarray analysis demonstrated that 1,25(OH)2D3 upregulated several genes directly related to glucose metabolism, tricarboxylic acid cycle (TCA), and oxidative phosphorylation (OXPHOS). Although OXPHOS was promoted by 1,25(OH)2D3, hypoxia did not change the tolerogenic function of 1,25(OH)2D3-treated DCs. Instead, glucose availability and glycolysis, controlled by the PI3K/Akt/mTOR pathway, dictate the induction and maintenance of the 1,25(OH)2D3-conditioned tolerogenic DC phenotype and function. This metabolic reprogramming is unique for 1,25(OH)2D3, because the tolerogenic DC phenotype induced by other immune modulators did not depend on similar metabolic changes. We put forward that these metabolic insights in tolerogenic DC biology can be used to advance DC-based immunotherapies, influencing DC longevity and their resistance to environmental metabolic stress.

PMID:
25660022
DOI:
10.1016/j.celrep.2015.01.013
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