Review
Regulation of the extrarenal CYP27B1-hydroxylase

https://doi.org/10.1016/j.jsbmb.2013.12.009Get rights and content

Highlights

  • We highlight translational research on the extrarenal CYP27B1-hydroxylase.

  • CYP27B1 orchestrates the intracrinology and paracrinology of vitamin D.

  • Macrophage CYP27B1 activity is a key to the immunobiology of vitamin D in man.

  • Principal factors controlling the CYP27B1 are 25OHD and Type I and Type II IFNs.

Abstract

Provided here is a collective review of research on the extrarenal CYP27B1-hydroxylase that shapes our current and expanding vision of the role this enzyme plays in the intracrinology and paracrinology, as opposed to the traditional endocrinology, of vitamin D to regulate the innate and adaptive immune responses, particularly in human granuloma-forming diseases like tuberculosis. Special emphasis is placed on soluble factors (i.e., cytokines) in the local microenvironment of these human diseases that coordinate amplification and feedback inhibition of the macrophage CYP27B1-hydroxylase. Principal among these factors are Type I and Type II interferons (IFNs); the Type II IFN, IFN-γ, stimulates the production of 1,25-dihydroxyvitamin D (1,25(OH)2D) from 25-hydroxyvitamin D (25OHD) by the granuloma-forming disease-activated macrophage, while the Type I IFNs, IFN-α and IFN-β, block the hydroxylation reaction. The Type I IFN response is associated with more aggressive disease, while the Type II IFN response, the one that promotes 1,25(OH)2D production by the macrophage, is associated with more confined disease. Tilting the balance in the human immune response toward a confined disease phenotype is enabled by the presence of sufficient extracellular 25OHD to modulate IFN-γ-promoted and substrate 25OH-driven intracellular synthesis of 1,25(OH)2D. This article is part of a Special Issue entitled ‘Vitamin D Workshop’.

Introduction

The first focus of this manuscript is to develop a retrospective view of the extrarenal CYP27B1-hydroxylase that shapes our current and expanding vision of the role this enzyme plays in the intracrinology and paracrinology of vitamin D: that is the role of the CYP27B1 in converting extracellular substrate 25-hydroxyvitamin D (25OHD) to 1,25-dihydroxyvitamin D (1,25(OH)2D) and the synthesized hormone then activating the vitamin D receptor (VDR) and downstream gene expression in the cell in which it was produced or in a neighboring, VDR-expressing cell. The second aim of this review is to describe evidence from “human experiments” of disease that expression of the CYP27B1 in extrarenal tissues and cells, especially the macrophage, underpins the emerging field of the immunobiology of vitamin D in man. The third goal of what follows is to model and describe in some molecular detail the mechanism by which the activity of macrophage CYP27B1 modulates both the innate and adaptive immune response to microbial challenge in humans, especially when conditioned ex vivo in human serum obtained from the same host before and after 25OHD replacement in vivo.

Section snippets

Immunobiology of vitamin D

Many, if not most, of the significant biological consequences of dysregulated vitamin D balance in man are associated with changes in the extracellular concentration of substrate 25OHD, not the active hormone, 1,25(OH)2D [1]. Therefore, from the intracrine point of view the entrance of free 25OHD into the cell, its conversion to 1,25(OH)2D and the interaction of 1,25(OH)2D with the VDR to regulate gene expression all occur in the cell interior, away from events that can be easily detected and

Human macrophage CYP27B1-hydroxylase and granuloma-forming disease

We entered the field in 1983 with publication of the observations (i) that macrophages harvested from the alveolar space of hypercalcemic patients with the granuloma-forming disease sarcoidosis were prolific synthesizers of 1,25(OH)2D ex vivo, (ii), compared to the renal 1-hydroxylation reaction, the synthesis of 1,25(OH)2D in the macrophage was 25OHD substrate-dependent and (iii) that a substantial portion of that endogenously synthesized hormone escaped the macrophage into the surrounding

Human macrophage and tuberculosis

The human pulmonary macrophage serves as a reserve for viable Mycobacterium tuberculosis (mTB) in infected humans. The mycobacteria are taken up by phagosomal vacuoles and reside there unless killed intracellularly. The fact is that roughly a third of the worlds’ population or 2.3 billion people carries live bacteria around in these phagosomal vacuoles without disease [13]. However, each year mycobacterium in only about a tenth of a percent of those infected (1.75 M individuals) escape

Human macrophage CYP27B1-hydroxylase: dependence on the extracellular 25OHD level

The above observations beg the question as to what serum levels of the 25OHD metabolite in living humans are sufficient to mount a cathelicidin response to a TLR challenge. We have now collected cathelicidin gene expression data (unpublished) in 19kD-TLR2/1-stimulated human macrophages conditioned in more than 100 human sera obtained before and after treatment in vivo with 500,000 IU vitamin D. Those sera contained increasing concentrations of total 25OHD, ranging from 5 to 95 ng/ml and total

Human macrophage CYP27B1-hydroxylase: concerted regulation ex vivo

What is the mechanism(s) by which TLR activation regulates CYP27B1 expression in the macrophage? Is the TLR2/1 signaling pathway the sole regulator of the CYP27B1 and VDR in human macrophages or is there concerted regulation of the vitamin D metabolic and gene regulatory pathway in macrophages? Krutzik and colleagues [22] discovered that TLR2/1-stimulated IL-15. Compared to other common cytokines that drive monocyte differentiation (IL-4 and GM-CSF), IL-15 had the greatest stimulatory effect on

Conclusions

In summary, while the Type II IFN, IFN-γ, stimulates the production of 1,25(OH)2D by the granuloma-forming disease-activated macrophage, the Type I IFNs -α and -β, use IL-10 to block the hydroxylation reaction. At least in the granuloma-forming disease, leprosy, the Type I IFN response is associated with more aggressive disease, while the Type II IFN, IFN-γ, promotes 1,25(OH)2D production by the cell and is associated with more confined disease [26], [27], [28]. If tilting the balance in the

Acknowledgements

Research reported in this publication was supported by the NIH under awards number TR000124, AI073539, AR059033 and AR063020. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.

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