Direct and Indirect Induction by 1,25-Dihydroxyvitamin D-3 of the NOD2/CARD15-Defensin beta 2 Innate Immune Pathway Defective in Crohn Disease

作者：Wang Tian Tian; Dabbas Basel; Laperriere David; Bitton Ari J; Soualhine Hafid; Tavera Mendoza Luz E; Dionne Serge; Servant Marc J; Bitton Alain; Seidman Ernest G; Mader Sylvie; Behr Marcel A; White John H^*

来源：JOURNAL OF BIOLOGICAL CHEMISTRY, 2010, 285(4): 2237-2241.

DOI：10.1074/jbc.C109.071225

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-kappa B transcription factor function, which induces expression of the gene encoding antimicrobial peptide defensin beta 2 (DEFB2/HBD2). Pretreatment with 1,25-dihydroxyvitamin D-3 synergistically induced NF-kappa B 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.

• 出版日期2010-1-22