The Vitamin D–antimicrobial Peptide Pathway and Its Role in Protection against Infection

Adrian F Gombart

Disclosures

Future Microbiol. 2009;4(9):1151-1165. 

In This Article

Vitamin D, Vitamin D Receptor & Immunity

Humans can obtain vitamin D in two different forms: vitamin D3, or cholecalciferol, and vitamin D2, or ergocalciferol. The former is synthesized in the skin by exposure to UVB radiation; the latter is produced in various plant materials, yeast and fungi when they are exposed to UVB radiation (Figure 1).[1] Humans can obtain both forms in the diet by consumption of either animal or plant products that possess them. Both forms of vitamin D are hydroxylated by the cytochrome P450 enzyme CYP27A1 in the liver to 25-hydroxyvitamin D (25[OH]D) in a substrate-dependent reaction (Figure 2).[1] The 25(OH)D circulates in the blood bound to the vitamin D-binding protein and is a reliable indicator of vitamin D status.[2] To become fully activated, the 25(OH)D is converted into 1,25-dihydroxyvitamin D (1,25[OH]2D) by the mitochondrial 1α-hydroxylase enzyme (CYP27B1) (Figure 2). The majority of the body's 1,25(OH)2D is synthesized in the primary renal tubules of the kidney, but synthesis also occurs in numerous extrarenal sites in cells that express CYP27B1.[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.

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.

The genomic actions of 1,25(OH)2D are modulated through the vitamin D receptor (VDR), a transcription factor belonging to the steroid/hormone receptor family.[3] Target genes contain vitamin D response elements (VDREs) in their promoters, to which heterodimers of VDR and retinoid X receptors (RXRs) can bind and transactivate expression of the target genes.[4] Most dividing cell types, normal and malignant, can express VDR and respond to 1,25(OH)2D, and the VDR is expressed in at least 30 different target tissues.[5,6]

Renal production of 1,25(OH)2D occurs in response to decreased levels of circulating Ca2+, which stimulates the production of parathyroid hormone (PTH). PTH induces the production of CYP27B1 by primary renal tubules. As circulating levels of 1,25(OH)2D rise, it suppresses its own production via a negative feedback loop in which the VDR binds to the CYP27B1 promoter to repress its expression. 1,25(OH)2D increases the uptake of Ca2+ by the intestine, which leads to a decrease in PTH levels. In addition, 1,25(OH)2D induces FGF-23 in osteocytes that represses PTH production. Furthermore, vitamin D induces the production of CYP24, a mitochondrial cytochrome P450 enzyme that catabolizes both 1,25(OH)2D and 25(OH)D, thus limiting its own production.[7]

Extrarenal production of vitamin D occurs in bone, epithelial cells of the skin, lung and colon, parathyroid glands and immune cells, especially activated macrophages. Control of its production in macrophages differs from renal tissues. Immune activation of macrophages with Toll-like receptor (TLR) ligands or IFN-γ leads to induction of CYP27B1 and production of 1,25(OH)2D and is dependent on the availability of 25(OH)D. CYP27B1 activity is not regulated by PTH or FGF-23 in macrophages and these cells synthesize an alternative splice variant of CYP24 that leads to the production of a dominant negative-acting protein that is catalytically inactive and prevents the catabolism of 1,25(OH)2D.[1,8] Thus, unlike renal tubules, macrophages do not limit their production of 1,25(OH)2D and their continued activation may lead to accumulation of 1,25(OH)2D and contribute to human disease.[8]

The importance of vitamin D and the active metabolite 1,25(OH)2D in immune function became apparent with the discovery of VDR expression in activated inflammatory cells.[9,10] Also, the VDR is expressed in most cells of the immune system.[11,12] Indeed, 1,25(OH)2D3 directly modulates T-cell proliferation and cytokine production, decreases Th1 development, inhibits Th17 development and enhances the frequency of Th2 and regulatory T-cell production.[13–17] A key mechanism in modulation of the adaptive immune system by vitamin receptor agonists involves their effects on myeloid dendritic cells (DCs).[18] Numerous studies have demonstrated that 1,25(OH)2D impacts DC phenotype and function by downregulating expression of costimulatory molecules (CD40, CD80 and CD86) and cytokine IL-12 and upregulating IL-10 levels (recently reviewed in[18]). The overall effect is to create tolerogenic myeloid DCs, which leads to decreased Th1 cell development, promotion of CD4+ suppressor T-cell activity and enhanced recruitment of regulatory T cells via increased expression of chemokine CCL22.[19–21] Protolerogenic, plasmacytoid DCs are negligibly affected by VDR agonists; thus, their tolerogenic potential is less likely to be modified.[18] The ability of 1,25(OH)2D to promote tolerance in DCs and T cells has prompted investigators to explore possible therapeutic treatments for a number of human autoimmune diseases.[11,21–23] Vitamin D inhibits proliferation and production of immunoglobulin and slows differentiation of B-cell precursors into plasma cells.[24] In addition to regulating their response to VDR agonists, macrophages, DCs and T cells can regulate the production and degradation of 1,25(OH)2D, which suggests an important biological role for 1,25(OH)2D in regulating innate and adaptive immunity.[25–30] Suppression of the adaptive immune system and the inflammatory action of the nuclear factor (NF)-κB pathway[31–33] by vitamin D are probably beneficial for conditions that involve autoimmunity;[34] however, it could prove detrimental for some infections.[35,36]

Contrary to its suppressive effects on adaptive immunity, vitamin D has been known to be important for protecting against infection. Prior to the development of antibiotics, cod liver oil, sunlight (both sources of vitamin D) and pharmacologic doses of vitamin D were used to treat TB.[37] This fell out of favor following the development of very effective antibiotic therapy. Recently, however, interest in using pharmacologic doses of vitamin D has been rekindled by discoveries made by our group and others that 1α,25-dihydroxyvitamin D can profoundly boost the innate immune system to combat pathogenic infections in vitro. The 'antibiotic' effect of vitamin D appears to be mediated, in part, by the induction of the human antimicrobial peptide genes.[25,38–41]

Vitamin D is critical for the regulation of both the CAMP and DEFB4 genes in both normal and transformed epithelial and hematopoietic cells.[38–40,42–44] This regulation is biologically important for the response of the innate immune system to wounds and infection.[25,43] Also, it may provide a mechanism to boost the innate immune system and counter the suppression of the adaptive immune system as described earlier.

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