Distinctive dendritic cell modulation by vitamin D(3) and glucocorticoid pathways.
Dendritic cell (DC) maturation plays a central role in regulating immunity. We show that glucocorticoid and 1alpha,25(OH)(2)D(3) agonists modulate DCs via distinct and additive signaling pathways. Phenotypic and functional indices were examined in DCs treated with dexamethasone (DEX) and/or a 1alpha,25(OH)(2)D(3) analog (D(3) analog). DEX potently attenuated pro-inflammatory cytokines and chemokines but had modest, reversible effects on T-cell stimulatory capacity. D(3) analog produced significantly greater inhibition of T-cell stimulation in vitro and in vivo and, unlike DEX, increased expression of the chemokines MCP-1 and MIP-1alpha. Both DEX and D(3) analog were associated with reduced expression of the NF-kappaB proteins c-Rel and Rel B but not Rel A. Combined DEX and D(3) analog treatment of DCs resulted in significant additive inhibition of pro-inflammatory cytokines, T-cell stimulation, chemokines, chemokine receptors, and NF-kappaB components. Additive inhibition was most striking for RANTES, CCR5, CCR7, and Rel B. The combined effects of the two hormonal pathways on DCs have unique immunomodulatory potential.
Xing
Nianzeng
N
Department of Internal Medicine, Division of Nephrology, Mayo Clinic and Foundation, Transplant Center, Charlton Building 10A, 200 First Street, Rochester, MN 55905, USA.
L  Maldonado
Monica L
ML
Bachman
Lori A
LA
McKean
David J
DJ
Kumar
Rajiv
R
Griffin
Matthew D
MD
D000818:Animals; D002478:Cells, Cultured; D018932:Chemokine CCL2 / Q000235:genetics; D054405:Chemokine CCL3; D054407:Chemokine CCL4; D018946:Chemokine CCL5 / Q000235:genetics; D002762:Cholecalciferol / Q000031:analogs & derivatives* / Q000494:pharmacology*; D017077:Culture Media, Conditioned; D003713:Dendritic Cells / Q000187:drug effects / Q000276:immunology*; D003907:Dexamethasone / Q000494:pharmacology*; D005786:Gene Expression Regulation / Q000187:drug effects* / Q000276:immunology; D005938:Glucocorticoids / Q000494:pharmacology; D019402:Macrophage Inflammatory Proteins / Q000235:genetics; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D011948:Receptors, Antigen, T-Cell / Q000235:genetics; D054389:Receptors, CCR1; D054390:Receptors, CCR2; D019707:Receptors, Chemokine / Q000235:genetics; D013601:T-Lymphocytes / Q000187:drug effects / Q000276:immunology*
C515301:Ccr1 protein, mouse; C515335:Ccr2 protein, mouse; D018932:Chemokine CCL2; D054405:Chemokine CCL3; D054407:Chemokine CCL4; D018946:Chemokine CCL5; D017077:Culture Media, Conditioned; D005938:Glucocorticoids; D019402:Macrophage Inflammatory Proteins; D011948:Receptors, Antigen, T-Cell; D054389:Receptors, CCR1; D054390:Receptors, CCR2; D019707:Receptors, Chemokine; D002762:Cholecalciferol; D003907:Dexamethasone