1-alpha,25-Dihydroxyvitamin D3 (1,25(OH)(2)D(3)) hampers the maturation of fully active immature dendritic cells from monocytes

Abstract

Objective: To study the effects of the active metabolite of vitamin D 3 , 1,25(OH) 2 D 3 , an immunomodulatory hormone, on the generation of so-called immature dendritic cells (iDCs) generated from monocytes (Mo-iDCs). Design and methods: Human peripheral blood monocytes were cultured to iDCs in the presence of granulocyte-macrophage colony-stimulating factor (GM-CSF) and interleukin (IL)-4 for 1 week, with or without the extra addition of 10 28 M 1,25(OH) 2 D 3 to the culture. Their phenotypes (CD14, CD1a, CD83, HLA-DR, CD80, CD86 and CD40 expression) were examined by¯uorescence-activated cell sorting, and their T-cell stimulatory potential was investigated in allogeneic mixed lymphocyte reaction (allo-MLR). Additionally, their in vitro production of IL-10, IL-12 and transforming growth factor b (TGF-b) were examined by using the enzyme-linked immunosorbent assay. Results: When 1,25(OH) 2 D 3 was added to monocytes in culture with GM-CSF and IL-4, it hampered the maturation of Mo-iDCs. First, the phenotype of the 1,25(OH) 2 D 3 -differentiated DCs was affected, there being impaired downregulation of the monocytic marker CD14 and impaired upregulation of the markers CD1a, CD83, HLA-DR, CD80 and CD40. CD86 was expressed on more 1,25(OH) 2 D 3 -differentiated DCs. Secondly, the T-cell stimulatory capability of 1,25(OH) 2 D 3 -differentiated DCs was upregulated relative to the original monocytes to a lesser degree than DCs differentiated without 1,25(OH) 2 D 3 when tested in an allo-MLR. With regard to the production of cytokines, Staphylococcus aureus cowan 1 strain (SAC)-induced IL-10 production, although not enhanced, remained high in 1,25(OH) 2 D 3 -differentiated DCs, but was strongly downregulated in DCs generated in the absence of 1,25(OH) 2 D 3 . SAC/interferon-g-induced IL-12 production was clearly upregulated in both types of DC relative to those of the original monocytes, and TGF-b production was downregulated. Conclusion: Our data con®rm earlier reports showing that 1,25(OH) 2 D 3 hampers the maturation of fully active immunostimulatory major histocompatibility complex (MHC) class II+, CD1a+, CD80+ DCs from monocytes. Our data supplement the data from other reports by showing that the expression of CD86 was upregulated in 1,25(OH) 2 D 3 -differentiated DCs, whilst the capacity for IL-10 production remained high. Collectively, these data are in line with earlier descriptions of suppressive activities of this steroid-like hormone with respect to the stimulation of cell-mediated immunity.

Flt3 ligand generates morphologically distinct semimature dendritic cells in ovalbumin-sensitized mice

“…Treatment of monocyte-derived DCs with 1, 25-dihydroxy vitamin D3 hampered maturation and also led to a reduction in the percentage of cells with cellular protrusions (Canning et al, 2001). On the contrary DCs generated from GM-CSF/IL4 and matured with TNF-α, LPS or CpG have a lot more dendrites (Weigel et al, 2002).…”

1α,25-Dihydroxyvitamin D3 modulates the murine antibody response to pneumococcal capsular polysaccharide serotype 3 through IL-12

“…Furthermore, 1a,25(OH) 2 D 3 has profound effects on DC, with strong inhibition of DC maturation and suppression of expression of MHCII, CD80, CD86 and CD83 [18,24,25].…”

Vitamin D and cardiovascular diseases

“…Prekomjerno stvaranje upalnih citokina doprinosi razvoju i progresiji zatajenja srca 40 . Eksperimentalne studije su pokazale da vitamin D igra vaaenu ulogu u regulaciji nekoliko vaaenih upalnih i protuupalnih citokina [41][42][43] . U jednoj studiji je opaaeena smanjena proizvodnja upalnih citokina (interleukin [IL]-6 i Ëimbenika tumorske nekroze [TNF] kada su aktivirani monociti bili izloaeeni kalcitriolu 42 .…”

“…U jednoj studiji je opaaeena smanjena proizvodnja upalnih citokina (interleukin [IL]-6 i Ëimbenika tumorske nekroze [TNF] kada su aktivirani monociti bili izloaeeni kalcitriolu 42 . SliËno, u drugoj studiji, produkcija protuupalnog citokina IL-10 se znaËajno poveÊala kada su dendritiËke stanice bile izloaeene kalcitriolu u usporedbi s kontrolnim stanicama koje nisu 41 . Ove studije su pokazale da hormonsko djelovanje vitamina D ima aktivnu i izravnu ulogu u regulaciji nekoliko imunomodulatorskih citokina πto dovodi do smanjenja upale.…”

“…Excessive production of inflammatory cytokines contributes to the development and progression of the heart failure 40 . Experimental studies have shown that vitamin D plays an important role in the regulation of several important inflammatory and anti-inflammatory cytokines [41][42][43] . One trial showed a decreased production of inflammatory cytokines (interleukin [IL]-6 and tumor necrosis factors [TNF] when the activated monocytes were exposed to calcitriol 42 .…”