Vitamin D and Crohn’s Disease

Direct and Indirect Induction by 1,25-Dihydroxyvitamin D3 of the NOD2/CARD15-Defensin β2 Innate Immune Pathway Defective in Crohn Disease*

1. Tian-Tian Wang‡,
2. Basel Dabbas‡,
3. David Laperriere§¶,
4. Ari J. Bitton‡,
5. Hafid Soualhine‖**,
6. Luz E. Tavera-Mendoza‡,
7. Serge Dionne‡‡§§,
8. Marc J. Servant¶¶,
9. Alain Bitton‡‡,
10. Ernest G. Seidman‖‡‡§§,
11. Sylvie Mader§¶,
12. Marcel A. Behr‖**‡‡ and
13. John H. White‡‡‡,1

+ Author Affiliations

1.
From the Departments of ‡Physiology and
2.
‡‡Medicine,
3.
‖Montreal General Hospital,
4.
**Division of Infectious Diseases and Medical Microbiology, and
5.
§§Division of Gastroenterology, McGill University, Montreal, Quebec H3G 1Y6 and
6.
the §Department of Biochemistry,
7.
¶Institute for Research in Immunology and Cancer, and
8.
¶¶Faculty of Pharmacy, University of Montreal, Montreal, Quebec H3C 3J7, Canada

1. 1 To whom correspondence should be addressed:
Dept. of Physiology, McGill University, 3655 Drummond St. Montreal, Quebec H3G 1Y6, Canada.
Tel.: 514-398-8498; Fax: 514-398-7452; E-mail: john.white@mcgill.ca.

Abstract

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 D3, 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-κB transcription factor function, which induces expression of the gene encoding antimicrobial peptide defensin β2 (DEFB2/HBD2). Pretreatment with 1,25-dihydroxyvitamin D3 synergistically induced NF-κB 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.


Dr. Darryl Roundy

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