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Review
. 2009 Nov;4(9):1151-65.
doi: 10.2217/fmb.09.87.

The vitamin D-antimicrobial peptide pathway and its role in protection against infection

Adrian F Gombart  1
Affiliations
Review

The vitamin D-antimicrobial peptide pathway and its role in protection against infection

Adrian F Gombart. Future Microbiol. 2009 Nov.

Abstract

Vitamin D deficiency has been correlated with increased rates of infection. Since the early 19th century, both environmental (i.e., sunlight) and dietary sources (cod liver) of vitamin D have been identified as treatments for TB. The recent discovery that vitamin D induces antimicrobial peptide gene expression explains, in part, the 'antibiotic' effect of vitamin D and has greatly renewed interest in the ability of vitamin D to improve immune function. Subsequent work indicates that this regulation is biologically important for the response of the innate immune system to wounds and infection and that deficiency may lead to suboptimal responses toward bacterial and viral infections. The regulation of the cathelicidin antimicrobial peptide gene is a human/primate-specific adaptation and is not conserved in other mammals. The capacity of the vitamin D receptor to act as a high-affinity receptor for vitamin D and a low-affinity receptor for secondary bile acids and potentially other novel nutritional compounds suggests that the evolutionary selection to place the cathelicidin gene under control of the vitamin D receptor allows for its regulation under both endocrine and xenobiotic response systems. Future studies in both humans and humanized mouse models will elucidate the importance of this regulation and lead to the development of potential therapeutic applications.

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Figures

Figure 1
Figure 1. Photoproduction of vitamin D
In plants or fungi, sunlight or artificial UVB rays cleave ergosterol in the B-ring to produce ergocalciferol or vitamin D2. In a very similar reaction in skin, 7-dehydrocholesterol is cleaved to produce cholecalciferol or vitamin D3. Both forms can be used as sources of vitamin D.
Figure 2
Figure 2. Conversion of vitamin D2 or vitamin D3 into active vitamin D
Vitamin D2 or vitamin D3 are hydroxylated in the liver by the enzyme CYP27A1 into 25-hydroxyvitamin D. This form of vitamin D circulates in the blood and is used to determine the vitamin D status of individuals (deficient: ≤20 ng/ml; insufficient: 21–29 ng/ml; sufficient: ≥30 ng/ml). When required by the body, the 25-hydroxyvitamin D form is converted by the CYP27B1 enzyme into the bioactive form, 1,25-dihydroxyvitamin D, which binds to the vitamin D receptor and activates gene expression. This primarily occurs in the kidney, but also occurs locally in cells that express CYP27B1. Immune-activated macrophages produce significant amounts of CYP27B1 and 1,25-dihydroxyvitamin D.
Figure 3
Figure 3. Vitamin D-dependent Toll-like receptor-activation of cathelicidin gene expression
The current model proposes that when a pathogen is detected by its respective TLR, VDR and CYP27B1 gene expression are induced. This leads to 1-α-hydroxylation of 25(OH)D, which is taken up from the blood (in a complex with the D-binding protein) and subsequent binding of 1,25(OH)2D to the VDR. The cathelicidin gene is activated and the protein (hCAP18/LL-37) is synthesized for use against the pathogen that has been engulfed in the phagosome of the macrophage. TLR: Toll-like receptor; VDR: Vitamin D receptor.
Figure 4
Figure 4. A role for enteric receptors in regulating the innate immune system by inducing antimicrobial gene expression
Intestinal detoxification receptors and the VDR share ligands and target genes. It has been shown that primary bile acids are capable of inducing cathelicidin gene expression in biliary epithelial cells through the FXR. Secondary bile acids that are byproducts of metabolism of primary bile acids by intestinal bacteria induce the cathelicidin gene via the VDR. The extensive crosstalk by these receptors possibly creates a system where bile acids, xenobiotic compounds and microbial byproducts can maintain critical gut immunity by inducing antimicrobial gene expression. FXR: Farnesoid X receptor; VDR: Vitamin D receptor; RXR: Retinoid X receptor.
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