Vitamin D3: a helpful immuno-modulator

Abstract

The active metabolite of vitamin D, 1α, 25-dihydroxyvitamin D3 [1,25(OH)(2) D3], is involved in calcium and phosphate metabolism and exerts a large number of biological effects. Vitamin D3 inhibits parathyroid hormone secretion, adaptive immunity and cell proliferation, and at the same time promotes insulin secretion, innate immunity and stimulates cellular differentiation. The role of vitamin D3 in immunoregulation has led to the concept of a dual function as both as an important secosteroid hormone for the regulation of body calcium homeostasis and as an essential organic compound that has been shown to have a crucial effect on the immune responses. Altered levels of vitamin D3 have been associated, by recent observational studies, with a higher susceptibility of immune-mediated disorders and inflammatory diseases. This review reports the new developments with specific reference to the metabolic and signalling mechanisms associated with the complex immune-regulatory effects of vitamin D3 on immune cells.

Figure 1

The biological action of 1,25(OH)₂D3. The ligand-bound vitamin D receptor (VDR) activates transcription by heterodimerization with RXRs, essential for high-affinity DNA binding to cognate vitamin D response elements (VDREs) located in the regulatory regions of 1,25D target genes. Ligand triggered conformational change of VDR–RXR heterodimers results in dissociation of nuclear receptor co-repressor (NCoR) and facilitates the interaction with members of the CBP/p300 and p160 co-activator families, including steroid receptor co-activators-1 (SRC-1), transcriptional intermediary factor 2 (TIF2), and receptor-activated co-activators-3 (RAC3).This activated complex recruits VDR-interacting protein (DRIP) and other co-regulatory proteins, which control histone modifications, chromatin remodelling, RNA polymerase II binding and transcriptional initiation. The complex VDR+RXR+1,25(OH)₂D3, targeting the DNA sequence of VDRE requires sufficient level of 1,25(OH)₂D to promote VDR signalling. Acetylated histones relax chromatin structure to make DNA accessible and permit initiation of transcription of the target gene.

Figure 2

1,25(OH)₂D3 intracellular signalling pathway. In response to 1,25(OH)₂D treatment viramin D receptor (VDR) interacts with phosphoinositide 3 (PI3) -kinase, its downstream element Akt kinase and with Src kinase. The expression of VDR in the cells increases in response to 1,25(OH)₂D3. It is unknown if VDR is translocated to the cell nucleus in response to 1,25(OH)₂D, or if it is continuously shuttled between cytosol and nucleus or if 1,25(OH)₂D traps it inside the nucleus. In the presence of 1,25(OH)₂D3, VDR/RXR heterodimers can displace DNA-bound nuclear factor of activated T cells.

Figure 3

Immune cell responses to pathogens: 25-hydroxyvitamin D (25OHD) binds vitamin D binding protein (VDBP), then is released into the cytosol and converted to 1,25(OH)₂D3 in the mitochondria. Vitamin D trigger pathogen-sensing via Toll-like receptor 2/1(TLR2/1) complex. Intracellular 1,25(OH)₂D3 generated though action of 25-hydroxyvitamin D-1 α-hydroxylase (CYP27B1) interacts with the 1,25(OH)₂D3 receptor (VDR). Activation of the VDR leads to induction of cathelicidin, which is the target for transcriptional regulation by 1,25(OH)₂D 3-liganded VDR. The induction of cathelicidin following localized synthesis of 1,25(OH)₂D3 promotes the generation of autophagosomes and enhances bacterial killing following generation of autolysosomes.

Figure 4

Effects of vitamin D on immune cells: (a) Macrophages and dendritic cells; (b) T lymphocytes, regulatory T (Treg) lymphocytes, B lymphocytes. CCR6, CCR10, chemokine receptor; CLA, conjugated linoleic acid; CDK-4,-6, cyclin-dependent kinase; ERN1, endoplasmic reticulum to nucleus signalling-1; FOXP3, forkhead box P-3; GM-CSF, granulocyte–macrophage colony-stimulating factor; DCs, dendritic cells; CYP24-SV, 24-hydroxylase splice variant form; CYP27B1, 25-hydroxyvitamin D-1 α-hydroxylase; Ig, immunoglobulin; iNOS, inducible nitric oxide synthases; IFN-γ, interferon-γ; IL-1, interleukin-1; LPS, lipopolysaccaride; MHC-2, major histocompatibility complex-2; MMP-7, matrix metalloproteinase-7; M. tb, Mycobacterium tuberculosis; NF-κB, nuclear factor-κB; NOD2/CARD15/IBD1, nucleotide-binding oligomerization domain containing 2/Caspase activation and recruitment domains/inflammatory bowel disease 1; Tregs, regulatory T cells; PAMPs, pathogen-associated molecular patterns; PBMC, peripheral blood mononuclear; PLC-γ1, phospholipase C-γ1; PGE₂, prostaglandin E₂; TCR, T-cell receptor; TLR-2, toll-like receptor-2; TGF-β₁, transforming growth factor-β₁; TNF-α, tumour necrosis-α; VDR, 1,25(OH)₂D3 receptor; Th-1, T helper type 1; XBP1, X-box binding protein-1.