Respiratory Epithelial Cells Convert Inactive Vitamin D to Its Active Form: Potential Effects on Host Defense

Abstract

(25D 3 ) 3 (2). The second step is conventionally known to take place in the kidneys, but increasing number of tissues have been found to express 1␣-hydroxylase (Cyp27B1), the enzyme responsible for the final and rate-limiting step in the synthesis of the active 1,25-dihydroxyvitamin D 3 (1,25D 3 ) (3, 4). Expression of 1␣-hydroxylase has been reported in epithelial cells of the skin (keratinocytes) (5, 6), intestine (7, 8), breast (9), and prostate (10) and in cells of the immune system including macrophages (11-13), monocytes VDR modulates the expression of a long list of genes in a celland tissue-specific manner. A number of these genes play a role in immunity. The first evidence suggesting that vitamin D has important immunomodulatory effects comes from epidemiological data showing that individuals with low 25D 3 levels are more susceptible to Mycbacterium tuberculosis infection and often have a more severe course of disease (20,21). Furthermore, several casecontrol studies have found an association between VDR polymorphisms and susceptibility to tuberculosis (22)(23)(24). A recent translational study indicates that the reason for these findings is insufficient levels of the antimicrobial protein, cathelicidin, in individuals with low vitamin D levels. In this study, activation of TLR2/1 by a mycobacterial ligand triggered up-regulation of cathelicidin mRNA and increased killing of mycobacteria by macrophages in the presence of vitamin D (25). A subsequent study in skin epithelial cells (keratinocytes) showed that skin injury or infection (TLR2/6 ligand) leads to activation of vitamin D and upregulation of at least two vitamin D-dependent genes, the cathelicidin antimicrobial peptide and the TLR coreceptor, CD14, involved in innate immunity (6). The genes encoding for cathelicidin (26 -28) and CD14 (29) have VDREs within their promoters and are positively regulated by vitamin D. Both are primarily expressed in myeloid cells but have also been found in respiratory

Serum vitamin D levels and exercise-induced bronchoconstriction in children with asthma

“…Fourthly, it has recently been observed that vitamin D3 diminishes endothelium-dependent contractions in the aorta by reducing calcium influx into the endothelial cells, hence decreasing the production of endothelium-derived contracting factors [27]. There are no reasons to exclude the possibility that these mechanisms may also be working in the airways, as vitamin D receptors are present in respiratory epithelial cells [28] and human bronchial smooth muscle cells, in which vitamin D regulates the expression of genes implicated in asthma pathogenesis [29]. Finally, several recent studies have established that vitamin D is a principal controller of innate immunity and adaptive immune responses [30].…”

Inverse relation between vitamin D and serum total immunoglobulin G in the Scandinavian Cystic Fibrosis Nutritional Study

“…Expression of CYP27B1, a 25OHD-activating enzyme, has been reported in normal human respiratory epithelial cells (Hansdottir et al, 2008), and active vitamin D has been found to induce antimicrobial peptide expression in CF bronchial epithelial cells (Yim et al, Inverse relation between vitamin D and serum IgG T Pincikova et al 2007). Moreover, vitamin D was shown to inhibit primarily production of the proinflammatory cytokines by adaptive immune cells and to decrease B-cell proliferation, plasmacell differentiation and IgG secretion (Mora et al, 2008).…”

“…However, several recent observations have initiated a re-evaluation of the physiological actions of vitamin D (Hansdottir et al, 2008;Mora et al, 2008). This was followed by subsequent description of 'non-classical functions of vitamin D', which include immunomodulatory properties of vitamin D, firmly supported by numerous in vitro and animal experiments (Bouillon et al, 2008).…”

The role of 1α,25‐dihydroxyvitamin D3 and cytokines in the promotion of distinct Foxp3+and IL‐10+CD4+T cells

“…Extrarenal synthesis of active vitamin D is increasingly being recognized as important for modulation of both innate and adaptive immunity [38]. Vitamin D3 can be metabolized into 1α25VitD3 by a variety of immune and structural cells including DCs [38,39], macrophages [40], and epithelial cells [41], which is proposed to result in relatively high 1α25VitD3 concentrated locally in the lymphoid microenvironment for presentation to interacting T-cells [42]. Thus, local synthesis of 1α25VitD3 in tissues may influence Treg frequency, although what constitutes "physiological" levels of 1α25VitD3 generated locally in tissues, and how these reflect observations from in vitro studies is as yet difficult to ascertain.…”