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Title: 1α,25-Dihydroxyvitamin D(3) and its analogs as modulators of human dendritic cells: A comparison dose-titration study
Authors: Bomfim Ferreira, Gabriela
Overbergh, Lut
Verstuyf, Annemieke #
Mathieu, Chantal # ×
Issue Date: Jul-2013
Publisher: Pergamon Press
Series Title: Journal of Steroid Biochemistry and Molecular Biology vol:136 pages:160-5
Article number: S0960-0760(12)00209-9
Abstract: The biologically active form of vitamin D, 1α,25-dihydroxyvitamin D(3) (1α,25(OH)(2)D(3)), presents pronounced immunomodulatory effects, mainly mediated through its actions on different immune cells such as dendritic cells (DC) and T lymphocytes. Because of the high concentrations needed to obtain immune effects, a major limitation in using 1α,25(OH)(2)D(3) in clinical immune therapy is its calcemic side effects. TX527 (19-nor-14,20-bis-epi-23-yne-1α,25(OH)(2)D(3)) is a structural 1α,25(OH)(2)D(3) analog showing reduced calcemic activity with maintained immunomodulatory effects in vitro and in vivo. The aim of the present study was to establish the relative potency of TX527 versus the parent molecule as an immunomodulator in vitro. In this regard, we evaluated the morphology, surface marker expression and reactive oxygen species (ROS) production in in vitro-generated human DCs treated with TX527 or 1α,25(OH)(2)D(3) at different concentrations. Human CD14(+) monocytes were differentiated toward immature DCs, in the presence or absence of 1α,25(OH)(2)D(3) or TX527 in a dose range from 10(-7)M to 10(-10)M. Mature DCs (mDC) were obtained after exposure of cells to LPS/interferon (IFN) γ or cluster of differentiation (CD) 40 ligand (L). Both compounds potently inhibited down-regulation of the monocytic marker CD14 in mDCs. Interestingly, CD80 and HLA-DR were down-regulated after TX527 treatment, whereas this effect was lost when using 1α,25(OH)(2)D(3) at the lowest concentration (10(-10)M). ROS production was especially induced in TX527-treated DCs, without any adverse effects on cell survival. Finally, this altered DC surface phenotype was accompanied by typical morphological features, with control cells forming large clusters of non-adherent cells, whereas TX527 and, to a lesser extent, 1α,25(OH)(2)D(3)-modulated cells yielding small clusters of mostly adherent spindle-shaped cells. This more pronounced immune potential in vitro combined with the previously shown decreased side effects on calcium and bone metabolism, makes TX527 a promising 1α,25(OH)(2)D(3) analog for in vivo applications in autoimmune diseases and transplantation. This article is part of a Special Issue entitled 'Vitamin D Workshop'.
URI: 
ISSN: 0960-0760
Publication status: published
KU Leuven publication type: IT
Appears in Collections:Clinical and Experimental Endocrinology
× corresponding author
# (joint) last author

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