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.
Highlights
Amongst the many reported extra-skeletal effects of vitamin D, its ability to regulate immunity through effects on both the innate and adaptive systems has received considerable attention
In 2006 the work of Finsen returned to center stage as a consequence of a series of genome-wide analyses that revealed pathogeninduction of an intracrine vitamin D system in monocytes (Liu et al, 2006), and an associated mechanism for anti-mycobacterial actions of vitamin D (Wang et al, 2004), whilst shedding light on how these responses may vary according to the vitamin D “status” of any given individual
In common with effects on expression of antibacterial proteins, it was noted that monocyte autophagy following activation of TLR2/1 involves enhanced expression of vitamin D receptor (VDR) and CYP27B1 (Shin et al, 2011), further highlighting the importance of intracrine 25-hydroxyvitamin D (25D) metabolism and action in normal human innate immunity
Summary
Amongst the many reported extra-skeletal effects of vitamin D, its ability to regulate immunity through effects on both the innate and adaptive systems has received considerable attention. 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.
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