Differential effect of vitamin D on NOD2- and TLR-induced cytokines in Crohn's disease.
Accumulating evidence implicates defective innate immunity in the pathogenesis of Crohn's disease (CD). Ineffectual NOD2 (nucleotide-binding oligomerization domain 2) is the most common susceptibility gene contributing to CD. Vitamin D (vD), a potent modulator of innate and adaptive immunity, induces NOD2 gene expression and its downstream function. We hypothesized that the hormonal form of vD (1,25D) could beneficially modulate innate immune function in CD. Using peripheral mononuclear cells and monocyte-derived dendritic cells (Mo-DCs) from CD, it was found that 1,25D decreased Toll-like receptor (TLR)-induced cytokine production and enhanced cytokine levels induced by muramyl dipeptide (MDP), the NOD2 ligand. 1,25D increased the synergistic effect provided by NOD2 and TLR co-activation on interleukin (IL)-10, IL-23, and tumor necrosis factor-alpha (TNF-α). Whereas 1,25D inhibits Mo-DC TLR-induced cytokines, co-stimulation of NOD2 results in increased IL-10 and IL-23. IL-12p70 was completely abrogated by 1,25D. 1,25D similarly modulated cytokine production by immune cells in ulcerative colitis patients and healthy controls. Mo-DCs from CD patients heterozygous for NOD2 mutations had a response similar to those from patients without NOD2 mutations. Immune cells from patients homozygous for the 1007 fs mutation were unresponsive to MDP and 1,25D. Our in vitro data support 1,25D as a potential modulator of immunity. However, these results cannot be extrapolated to CD patients without further controlled studies.
McGill Center for IBD Research, Research Institute of the McGill University Health Center, McGill University, Montreal, Quebec, Canada.
S
S
Dionne
Department of Physiology, Faculty of Medicine, McGill University, Montreal, Quebec, Canada.
M R
MR
Calderon
Department of Physiology, Faculty of Medicine, McGill University, Montreal, Quebec, Canada.
J H
JH
White
Department of Physiology, Faculty of Medicine, McGill University, Montreal, Quebec, Canada.
B
B
Memari
McGill Center for IBD Research, Research Institute of the McGill University Health Center, McGill University, Montreal, Quebec, Canada.
I
I
Elimrani
McGill Center for IBD Research, Research Institute of the McGill University Health Center, McGill University, Montreal, Quebec, Canada.
B
B
Adelson
McGill Center for IBD Research, Research Institute of the McGill University Health Center, McGill University, Montreal, Quebec, Canada.
C
C
Piccirillo
McGill Center for IBD Research, Research Institute of the McGill University Health Center, McGill University, Montreal, Quebec, Canada.
E G
EG
Seidman
D002117:Calcitriol / Q000494:pharmacology*; D002478:Cells, Cultured; D003424:Crohn Disease / Q000188:drug therapy / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D016207:Cytokines / Q000235:genetics / Q000276:immunology*; D003713:Dendritic Cells / Q000276:immunology / Q000473:pathology; D005260:Female; D006801:Humans; D007155:Immunologic Factors / Q000494:pharmacology*; D008297:Male; D009154:Mutation; D053473:Nod2 Signaling Adaptor Protein / Q000235:genetics / Q000276:immunology*; D051193:Toll-Like Receptors / Q000235:genetics / Q000276:immunology*; D014815:Vitamins / Q000494:pharmacology
D016207:Cytokines; D007155:Immunologic Factors; C429018:NOD2 protein, human; D053473:Nod2 Signaling Adaptor Protein; D051193:Toll-Like Receptors; D014815:Vitamins; D002117:Calcitriol