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
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.
Available from: Meg Mangin
- "Crohn’s disease decreases expression of cathelicidin . "
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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.
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.
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.
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
Available from: Anna K Coussens
- "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
(MTB) infection. Moreover, maintaining vitamin D sufficiency prior to MTB infection enhances the innate antimicrobial response to T cell-mediated interferon-
. 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.
07/2014; 2014(12):903680. DOI:10.1155/2014/903680
Available from: Rene F Chun
- "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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ABSTRACT: Immunomodulatory responses to the active form of vitamin D (1,25-dihydroxyvitamin D, 1,25D) have been recognized for many years, but it is only in the last 5 years that the potential role of this in normal human immune function has been recognized. Genome-wide analyses have played a pivotal role in redefining our perspective on vitamin D and immunity. The description of increased vitamin D receptor (VDR) and 1α-hydroxylase (CYP27B1) expression in macrophages following a pathogen challenge, has underlined the importance of intracrine vitamin D as key mediator of innate immune function. It is now clear that both macrophages and dendritic cells (DCs) are able to respond to 25-hydroxyvitamin D (25D), the major circulating vitamin D metabolite, thereby providing a link between the function of these cells and the variations in vitamin D status common to many humans. The identification of hundreds of primary 1,25D target genes in immune cells has also provided new insight into the role of vitamin D in the adaptive immune system, such as the modulation of antigen-presentation and T cells proliferation and phenotype, with the over-arching effects being to suppress inflammation and promote immune tolerance. In macrophages 1,25D promotes antimicrobial responses through the induction of antibacterial proteins, and stimulation of autophagy and autophagosome activity. In this way variations in 25D levels have the potential to influence both innate and adaptive immune responses. More recent genome-wide analyses have highlighted how cytokine signaling pathways can influence the intracrine vitamin D system and either enhance or abrogate responses to 25D. The current review will discuss the impact of intracrine vitamin D metabolism on both innate and adaptive immunity, whilst introducing the concept of disease-specific corruption of vitamin D metabolism and how this may alter the requirements for vitamin D in maintaining a healthy immune system in humans.
Frontiers in Physiology 04/2014; 5:151. DOI:10.3389/fphys.2014.00151 · 3.53 Impact Factor
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