1,25-Dihydroxyvitamin D3 selectively modulates tolerogenic properties in myeloid but not plasmacytoid dendritic cells.
1,25-Dihydroxyvitamin D(3) (1,25(OH)(2)D(3)) is an immunomodulatory agent inducing dendritic cells (DCs) to become tolerogenic. To further understand its mechanisms of action, we have examined the effects of 1,25(OH)(2)D(3) on tolerogenic properties of blood myeloid (M-DCs) and plasmacytoid (P-DCs) human DC subsets. Exposure of M-DCs to 1,25(OH)(2)D(3) up-regulated production of CCL22, a chemokine attracting regulatory T cells, whereas production of CCL17, the other CCR4 ligand, was reduced. 1,25(OH)(2)D(3) also decreased IL-12p75 production by M-DCs, as expected, and inhibited CCR7 expression. 1,25(OH)(2)D(3) treatment markedly increased CD4(+) suppressor T cell activity while decreasing the capacity of M-DCs to induce Th1 cell development. Surprisingly, 1,25(OH)(2)D(3) did not exert any discernible effect on tolerogenic properties of P-DCs, and even their high production of IFN-alpha was not modulated. In particular, the intrinsically high capacity of P-DCs to induce CD4(+) suppressor T cells was unaffected by 1,25(OH)(2)D(3). Both DC subsets expressed similar levels of the vitamin D receptor, and its ligation by 1,25(OH)(2)D(3) similarly activated the primary response gene cyp24. Interestingly, 1,25(OH)(2)D(3) inhibited NF-kappaB p65 phosphorylation and nuclear translocation in M-DCs but not P-DCs, suggesting a mechanism for the inability of 1,25(OH)(2)D(3) to modulate tolerogenic properties in P-DCs.
Penna
Giuseppe
G
BioXell, Milan, Italy.
Amuchastegui
Susana
S
Giarratana
Nadia
N
Daniel
Kenn C
KC
Vulcano
Marisa
M
Sozzani
Silvano
S
Adorini
Luciano
L
D021581:Active Transport, Cell Nucleus; D015704:CD4 Antigens / Q000032:analysis; D002117:Calcitriol / Q000494:pharmacology* / Q000502:physiology*; D054414:Chemokine CCL17; D054422:Chemokine CCL22; D019742:Chemokines, CC / Q000378:metabolism; D003713:Dendritic Cells / Q000187:drug effects* / Q000276:immunology; D015870:Gene Expression / Q000187:drug effects; D000949:Histocompatibility Antigens Class II / Q000235:genetics; D006801:Humans; D007108:Immune Tolerance / Q000187:drug effects*; D007165:Immunosuppression Therapy; D008024:Ligands; D008562:Membrane Glycoproteins; D022423:Myeloid Cells / Q000187:drug effects* / Q000276:immunology; D016328:NF-kappa B / Q000378:metabolism; D010766:Phosphorylation; D010950:Plasma Cells / Q000187:drug effects / Q000276:immunology; D054398:Receptors, CCR4; D018167:Receptors, Calcitriol / Q000819:agonists; D011956:Receptors, Cell Surface / Q000235:genetics; D019707:Receptors, Chemokine / Q000378:metabolism; D011971:Receptors, Immunologic; D018417:Th1 Cells / Q000187:drug effects / Q000276:immunology; D014158:Transcription, Genetic / Q000187:drug effects
C106230:CCL17 protein, human; C515482:CCL22 protein, human; C515354:CCR4 protein, human; D015704:CD4 Antigens; D054414:Chemokine CCL17; D054422:Chemokine CCL22; D019742:Chemokines, CC; D000949:Histocompatibility Antigens Class II; C107907:LILRB4 protein, human; D008024:Ligands; D008562:Membrane Glycoproteins; D016328:NF-kappa B; D054398:Receptors, CCR4; D018167:Receptors, Calcitriol; D011956:Receptors, Cell Surface; D019707:Receptors, Chemokine; D011971:Receptors, Immunologic; D002117:Calcitriol