Suppressive effect of 1alpha,25-dihydroxyvitamin D3 on type I IFN-mediated monocyte differentiation into dendritic cells: impairment of functional activities and chemotaxis.
Dendritic cells (DCs) generated by a single-step exposure of human monocytes to type I IFN and GM-CSF (IFN-DCs) are endowed with potent immunostimulatory activities and a distinctive migratory response to specific chemokines. In this study, we evaluated the effects of 1alpha,25-dihydroxyvitamin D(3) (1,25(OH)(2)D(3)), the biologically active metabolite of vitamin D(3), on the DC differentiation/activation induced by type I IFN. We found that 1,25(OH)(2)D(3) prevented the generation of IFN-DCs when added to freshly isolated monocytes, and was capable of redirecting already differentiated IFN-DCs toward a more immature stage, as revealed by their immunophenotype, reduced allostimulatory activity, and impaired LPS-induced production of Th1-polarizing cytokines. Control and 1,25(OH)(2)D(3)-treated IFN-DCs exhibited a similar expression of vitamin D receptor, as well as comparable cell death rates. Furthermore, the chemotactic response of IFN-DCs to CCL4 and CCL19 was markedly reduced or completely abrogated by 1,25(OH)(2)D(3). Despite these changes in the IFN-DC migratory behavior, the expression of CCR5 and CCR7 and the calcium fluxes triggered by CCL4 and CCL19 were not affected. These findings indicate that, in this innovative single-step DC generation model from monocytes, the suppressive effect of 1,25(OH)(2)D(3) is associated with a potent impairment of DC migration in response to inflammatory and lymph node-homing chemokines, thus unraveling a novel mechanism involved in 1,25(OH)(2)D(3)-mediated immunomodulation.
Gauzzi
Maria Cristina
MC
Department of Cell Biology and Neurosciences, Istituto Superiore di Sanità, Viale Regina Elena 299, 00161 Rome, Italy.
Purificato
Cristina
C
Donato
Karim
K
Jin
Yixin
Y
Wang
Ling
L
Daniel
Kenn C
KC
Maghazachi
Azzam A
AA
Belardelli
Filippo
F
Adorini
Luciano
L
Gessani
Sandra
S
D002454:Cell Differentiation / Q000187:drug effects; D018925:Chemokines / Q000276:immunology / Q000378:metabolism; D002634:Chemotaxis, Leukocyte / Q000187:drug effects*; D003713:Dendritic Cells / Q000166:cytology* / Q000187:drug effects / Q000276:immunology; D005434:Flow Cytometry; D006801:Humans; D007370:Interferon Type I / Q000276:immunology*; D007959:Lymphocyte Culture Test, Mixed; D009000:Monocytes / Q000166:cytology* / Q000187:drug effects / Q000276:immunology; D018167:Receptors, Calcitriol / Q000276:immunology / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014807:Vitamin D / Q000494:pharmacology*
D018925:Chemokines; D007370:Interferon Type I; D018167:Receptors, Calcitriol; D014807:Vitamin D