Direct and indirect induction by 1,25-dihydroxyvitamin D3 of the NOD2/CARD15-defensin beta2 innate immune pathway defective in Crohn disease.
Vitamin D signaling through its nuclear vitamin D receptor has emerged as a key regulator of innate immunity in humans. Here we show that hormonal vitamin D, 1,25-dihydroxyvitamin D(3), robustly stimulates expression of pattern recognition receptor NOD2/CARD15/IBD1 gene and protein in primary human monocytic and epithelial cells. The vitamin D receptor signals through distal enhancers in the NOD2 gene, whose function was validated by chromatin immunoprecipitation and chromatin conformation capture assays. A key downstream signaling consequence of NOD2 activation by agonist muramyl dipeptide is stimulation of NF-kappaB transcription factor function, which induces expression of the gene encoding antimicrobial peptide defensin beta2 (DEFB2/HBD2). Pretreatment with 1,25-dihydroxyvitamin D(3) synergistically induced NF-kappaB function and expression of genes encoding DEFB2/HBD2 and antimicrobial peptide cathelicidin in the presence of muramyl dipeptide. Importantly, this synergistic response was also seen in macrophages from a donor wild type for NOD2 but was absent in macrophages from patients with Crohn disease homozygous for non-functional NOD2 variants. These studies provide strong molecular links between vitamin D deficiency and the genetics of Crohn disease, a chronic incurable inflammatory bowel condition, as Crohn's pathogenesis is associated with attenuated NOD2 or DEFB2/HBD2 function.
Wang
Tian-Tian
TT
Department of Physiology, Montreal General Hospital, Canada.
Dabbas
Basel
B
Laperriere
David
D
Bitton
Ari J
AJ
Soualhine
Hafid
H
Tavera-Mendoza
Luz E
LE
Dionne
Serge
S
Servant
Marc J
MJ
Bitton
Alain
A
Seidman
Ernest G
EG
Mader
Sylvie
S
Behr
Marcel A
MA
White
John H
JH
D000119:Acetylmuramyl-Alanyl-Isoglutamine / Q000494:pharmacology; D000276:Adjuvants, Immunologic / Q000494:pharmacology; D002117:Calcitriol / Q000378:metabolism / Q000494:pharmacology*; D003424:Crohn Disease / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D004357:Drug Synergism; D004847:Epithelial Cells / Q000276:immunology; D006801:Humans; D008264:Macrophages / Q000276:immunology / Q000378:metabolism; D009000:Monocytes / Q000276:immunology / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism; D053473:Nod2 Signaling Adaptor Protein / Q000235:genetics*; D015398:Signal Transduction / Q000276:immunology; D015533:Transcriptional Activation / Q000276:immunology; D014808:Vitamin D Deficiency / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D023083:beta-Defensins / Q000235:genetics*
D000276:Adjuvants, Immunologic; C106641:DEFB4A protein, human; D016328:NF-kappa B; C429018:NOD2 protein, human; D053473:Nod2 Signaling Adaptor Protein; D023083:beta-Defensins; D000119:Acetylmuramyl-Alanyl-Isoglutamine; D002117:Calcitriol