Direct and Indirect Induction by 1,25-Dihydroxyvitamin D3 of the NOD2/CARD15-Defensin 2 Innate Immune Pathway Defective in Crohn Disease

Department of Physiology, Montreal General Hospital, Canada.
Journal of Biological Chemistry (Impact Factor: 4.57). 11/2009; 285(4):2227-31. DOI: 10.1074/jbc.C109.071225
Source: PubMed


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.

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    • "Crohn’s disease decreases expression of cathelicidin [121]. "
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    ABSTRACT: Introduction: Inflammation is believed to be a contributing factor to many chronic diseases. The influence of vitamin D deficiency on inflammation is being explored but studies have not demonstrated a causative effect. Methods: Low serum 25(OH)D is also found in healthy persons exposed to adequate sunlight. Despite increased vitamin D supplementation inflammatory diseases are increasing. The current method of determining vitamin D status may be at fault. The level of 25(OH)D does not always reflect the level of 1,25(OH)2D. Assessment of both metabolites often reveals elevated 1,25(OH)2D, indicating abnormal vitamin D endocrine function. Findings: This article reviews vitamin D's influence on the immune system, examines the myths regarding vitamin D photosynthesis, discusses ways to accurately assess vitamin D status, describes the risks of supplementation, explains the effect of persistent infection on vitamin D metabolism and presents a novel immunotherapy which provides evidence of an infection connection to inflammation. Conclusion: Some authorities now believe that low 25(OH)D is a consequence of chronic inflammation rather than the cause. Research points to a bacterial etiology pathogenesis for an inflammatory disease process which results in high 1,25(OH)2D and low 25(OH)D. Immunotherapy, directed at eradicating persistent intracellular pathogens, corrects dysregulated vitamin D metabolism and resolves inflammatory symptoms.
    Inflammation Research 07/2014; 63(10). DOI:10.1007/s00011-014-0755-z · 2.35 Impact Factor
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    • "In addition to CAMP induction, 1,25[OH]2D has also been shown to increase expression of another antimicrobial peptide beta-defensin 2 (DEFB4) [78, 81, 82]. In comparison to CAMP, the DEFB4 promoter only has one VDRE but two NF-κB binding sites. "
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    07/2014; 2014(12):903680. DOI:10.1155/2014/903680
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    • "By contrast, induction of CAMP appears to be primarily dependent on binding of VDR to promoter VDRE (Liu et al., 2009). The importance of NF-κB and VDR as co-inducers of DEFB4 transcription was further emphasized by studies of the intracellular pathogen sensing protein NOD2 which is itself transcriptionally induced by 1,25D (Wang et al., 2010b). Cells co-treated with 1,25D and the ligand for NOD2, muramyl dipeptide (MDP), a cell wall product of Gram-positive and Gram-negative bacteria, showed potent NF-κB-dependent induction of DEFB4 (Wang et al., 2010b). "
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