Article

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

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 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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    • "Consequently, vitamin D during pregnancy influences both arms of the immune system, which is involved in implantation as well as in responses to infection or inflammation [113]. In utero, the local synthesis of 1,25(OH) 2 D by placental monocytes also promotes the transcription of genes coding for cathelicidin [114] and β-defensin [115] and regulates the autophagy for pathogen killing [116]. Due to the fact that heterogenous cellular types constitute the placenta, a wide range of cells expressing TLRs have the necessary armamentarium to respond to infections and induce the local production of 1,25(OH) 2 D [22]. "
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    ABSTRACT: Vitamin D has an indisputable immunodulatory role in both lung and immune system development, which is initiated during fetal life and is mainly accomplished in the first years of extrauterine life. Several published studies have shown that low levels of vitamin D may increase the risk of developing asthma and allergic diseases. Moreover, vitamin D deficiency epidemic reported over the last decades coincides with an increase in the prevalence of asthma and allergies in westernized societies. Since placental transfer of 25(OH)D is the major source of vitamin D in the developing fetus, important questions concerning the impact of maternal vitamin D status on the outcome of pregnancy have arisen. The aim of this review is to present the current evidence regarding the determinants of vitamin D status in pregnancy as well as its role in the development of asthma and allergies in early childhood.
    Full-text · Article · May 2015 · Mini Reviews in Medicinal Chemistry
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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.
    Full-text · Article · Jul 2014 · Inflammation Research
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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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    ABSTRACT: Tuberculosis (TB) disease activation is now believed to arise due to a lack of inflammatory homeostatic control at either end of the spectrum of inflammation: either due to immunosuppression (decreased antimicrobial activity) or due to immune activation (excess/aberrant inflammation). Vitamin D metabolites can increase antimicrobial activity in innate immune cells, which, in the context of HIV-1 coinfection, have insufficient T cell-mediated help to combat Mycobacterium tuberculosis (MTB) infection. Moreover, maintaining vitamin D sufficiency prior to MTB infection enhances the innate antimicrobial response to T cell-mediated interferon- γ . Conversely, vitamin D can act to inhibit expression and secretion of a broad range of inflammatory mediators and matrix degrading enzymes driving immunopathology during active TB and antiretroviral- (ARV-) mediated immune reconstitution inflammatory syndrome (IRIS). Adjunct vitamin D therapy during treatment of active TB may therefore reduce lung pathology and TB morbidity, accelerate resolution of cavitation and thereby decrease the chance of transmission, improve lung function following therapy, prevent relapse, and prevent IRIS in those initiating ARVs. Future clinical trials of vitamin D for TB prevention and treatment must be designed to detect the most appropriate primary endpoint, which in some cases should be anti-inflammatory and not antimicrobial.
    Full-text · Article · Jul 2014
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