Human dendritic cell antigen presentation and chemotaxis are inhibited by intrinsic 25-hydroxy vitamin D activation.
The immunomodulatory effects of vitamin D have primarily been investigated using the biologically active form 1,25-dihydroxy vitamin D3 (1,25-D3). It was recently demonstrated that dendritic cells (DC) are able to convert the inactive 25-hydroxy vitamin D3 (25-D3) into the active form via 1 alpha-hydroxylase. In this study, we set out to examine the possible consequences of this conversion on adaptive immune functions. Human monocyte-derived DC were matured by lipopolysaccharide (LPS) in the presence or absence of 25-D3. Subsequently, the conversion of 25-D3 into 1,25-D3, and the effects on surface marker expression, cytokine production, antigen-presenting capacity and chemotaxis of the DC were examined. 25-D3 was clearly converted into 1,25-D3 in the DC cultures and the process was accompanied by a reduced expression of CD80 (p<0.01), CD83 (p<0.01), CD86 (p=0.02), and HLA-DR (p=0.02). Also, the levels of the pro-inflammatory cytokines tumour necrosis factor (TNF) alpha (p=0.02) and interleukin (IL) 12 (p<0.01) were reduced. Interestingly, however, the CD14 expression (p<0.01) and the production of IL-1 beta (p<0.01) and IL-6 (p<0.01) increased. Thus, 25-D3 affected the delicate interplay between anti- and pro-inflammatory cytokines produced by the DC. Concurrently, 25-D3 reduced DC capacity to induce proliferation of antigen-specific T cells and DC chemotaxis towards chemokine (CC) ligand 21. This indicates that 25-D3 has a regulating function following intrinsic 1 alpha-hydroxylation, a mechanism that potentially has an immunomodulatory effect in vivo.
Bartels
Lars E
LE
Laboratory of Immunology, Aalborg University, Fredrik Bajers Vej 3B, 9220 Aalborg Ø, Denmark. bartels@ki.au.dk
Hvas
Christian L
CL
Agnholt
Jørgen
J
Dahlerup
Jens F
JF
Agger
Ralf
R
D017951:Antigen Presentation / Q000187:drug effects; D015703:Antigens, CD / Q000096:biosynthesis* / Q000235:genetics; D000943:Antigens, Differentiation / Q000096:biosynthesis* / Q000235:genetics; D002454:Cell Differentiation / Q000187:drug effects / Q000276:immunology; D002478:Cells, Cultured; D054421:Chemokine CCL21 / Q000378:metabolism; D002633:Chemotaxis / Q000187:drug effects; D002762:Cholecalciferol / Q000031:analogs & derivatives / Q000378:metabolism / Q000494:pharmacology*; D053493:Cholestanetriol 26-Monooxygenase / Q000378:metabolism*; D016207:Cytokines / Q000096:biosynthesis / Q000235:genetics; D003713:Dendritic Cells / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D006801:Humans; D056747:Immunomodulation; D008070:Lipopolysaccharides / Q000276:immunology / Q000378:metabolism; D009000:Monocytes / Q000473:pathology
D015703:Antigens, CD; D000943:Antigens, Differentiation; D054421:Chemokine CCL21; D016207:Cytokines; D008070:Lipopolysaccharides; D002762:Cholecalciferol; D053493:Cholestanetriol 26-Monooxygenase