1,25-Dihydroxyvitamin D3 inhibits dendritic cell differentiation and maturation in vitro

Berer, A.; Stöckl, Johannes; Majdic, Otto; Wagner, Thomas; Kollars, Marietta; Lechner, Klaus; Geißler, Klaus; Oehler, Leopold

doi:10.1016/s0301-472x(00)00143-0

Cited by 199 publications

(149 citation statements)

References 50 publications

(41 reference statements)

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“…Piemonti (11) found that the expression of CD86 was inhibited in the presence of 1,25(OH) 2 D 3 , but that the expression of CD80 was not signi®cantly affected. This is in contrast to data from Berer (12), who found that CD86 expression was unaffected by 1,25(OH) 2 D 3 , whereas upregulation of CD80 was prevented. Immature DCs can be further differentiated into mature DCs in vitro by culturing them with lipopolysaccharide, TNF-a, IL-1 or CD40-ligand (13,14).…”

contrasting

confidence: 99%

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

Canning

Grotenhuis

Wit

et al. 2001

European Journal of Endocrinology

215

142

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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.

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contrasting

confidence: 99%

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

Canning

Grotenhuis

Wit

et al. 2001

European Journal of Endocrinology

215

142

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“…This may explain in part the relative resistance of immature DCs as compared with monocyte precursors to the inhibitory effects of the ligand. Although immature DCs still retain some sensitivity to 1␣25(OH) 2 D 3 (5,6,44), mature DCs are almost completely resistant to its inhibitory effects (44) despite similar expression of VDR. Thus, other factors, including expression of partner receptors/coactivators or the integrity of downstream signaling pathways, are likely to contribute to this resistance.…”

Section: Discussionmentioning

confidence: 99%

Differential Regulation of Vitamin D Receptor and Its Ligand in Human Monocyte-Derived Dendritic Cells

Hewison

Freeman²,

Hughes

et al. 2003

The Journal of Immunology

411

340

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The functions of dendritic cells (DCs) are tightly regulated such that protective immune responses are elicited and unwanted immune responses are prevented. 1α25-dihydroxyvitamin D3 (1α25(OH)2D3) has been identified as a major factor that inhibits the differentiation and maturation of DCs, an effect dependent upon its binding to the nuclear vitamin D receptor (VDR). Physiological control of 1α25(OH)2D3 levels is critically dependent upon 25-hydroxyvitamin D3-1α-hydroxylase (1αOHase), a mitochondrial cytochrome P450 enzyme that catalyzes the conversion of inactive precursor 25-hydroxyvitamin D3 (25(OH)D3) to the active metabolite 1α25(OH)2D3. Using a human monocyte-derived DC (moDC) model, we have examined the relationship between DC VDR expression and the impact of exposure to its ligand, 1α25(OH)2D3. We show for the first time that moDCs are able to synthesize 1α25(OH)2D3 in vitro as a consequence of increased 1αOHase expression. Following terminal differentiation induced by a diverse set of maturation stimuli, there is marked transcriptional up-regulation of 1αOHase leading to increased 1αOHase enzyme activity. Consistent with this finding is the observation that the development and function of moDCs is inhibited at physiological concentrations of the inactive metabolite 25(OH)D3. In contrast to 1αOHase, VDR expression is down-regulated as monocytes differentiate into immature DCs. Addition of 1α25(OH)2D3 to moDC cultures at different time points indicates that its inhibitory effects are greater in monocyte precursors than in immature DCs. In conclusion, differential regulation of endogenous 1α25(OH)2D3 ligand and its nuclear receptor appear to be important regulators of DC biology and represent potential targets for the manipulation of DC function.

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“…1,25(OH) 2 D 3 also regulates antigen-presenting cells such as macrophages and dendritic cells. It inhibits dendritic cell differentiation from peripheral blood monocytes and suppresses the production of IL-12, a cytokine crucial for the development of Th1 cells (1,7,33,34). Consistent with its anti-inflammatory role, 1,25(OH) 2 D 3 downregulates the expression of many other proinflammatory cytokines such as IL-1, IL-6, IL-8, and TNF-␣ in a variety of cell types (9,12).…”

mentioning

confidence: 92%

Increased NF-κB activity in fibroblasts lacking the vitamin D receptor

Sun

Kong

Duan³

et al. 2006

American Journal of Physiology-Endocrinology and Metabolism

213

194

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1,25-Dihydroxyvitamin D [1,25(OH)2D3] is known to have anti-inflammatory activity; however, the molecular mechanism remains poorly defined. Here we show that the nuclear vitamin D receptor (VDR) is directly involved in the regulation of NF-κB activation, a pathway essential for inflammatory response. In mouse embryonic fibroblasts (MEFs) derived from VDR−/− mice, the basal level of κB inhibitor (IκB) α protein was markedly decreased compared with VDR+/− MEFs; however, degradation of IκBα and its phosphorylation in response to TNF-α treatment or Salmonella infection were not altered in VDR−/− cells, neither were the levels of IκB kinase-α and IκB kinase-β proteins. Consistent with IκBα reduction, p65 accumulation in the nucleus was markedly increased in unstimulated VDR−/− cells. In addition, the physical interaction between VDR and p65 was absent in VDR−/− MEFs, which may free p65 and increase its activity. Consequently, these alterations combined led to a marked increase in nuclear p65 DNA binding and NF-κB transcriptional activity; consistently, induction of IL-6 by TNF-α or IL-1β was much more robust in VDR−/− than in VDR+/− cells, indicating that VDR−/− cells are more susceptible to inflammatory stimulation. Therefore, cells lacking VDR appear to be more proinflammatory due to the intrinsic high NF-κB activity. The reduction of IκBα in VDR−/− MEFs may be partially explained by the lack of VDR-mediated stabilization of IκBα by 1,25(OH)2D3. This is supported by the observation that IκBα degradation induced by TNF-α was inhibited by 1,25(OH)2D3 in VDR+/− cells, but not in VDR−/− cells. Taken together, these data suggest that VDR plays an inhibitory role in the regulation of NF-κB activation.

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1,25-Dihydroxyvitamin D3 inhibits dendritic cell differentiation and maturation in vitro

Cited by 199 publications

References 50 publications

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

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

Differential Regulation of Vitamin D Receptor and Its Ligand in Human Monocyte-Derived Dendritic Cells

Increased NF-κB activity in fibroblasts lacking the vitamin D receptor

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