The Impact of Vitamin D Levels on Inflammatory Status: A Systematic Review of Immune Cell Studies

Abstract

Chronic low-grade inflammation accompanies obesity and its related chronic conditions. Both peripheral blood mononuclear cells (PBMCs) and cell lines have been used to study whether vitamin D has immune modulating effects; however, to date a detailed systematic review describing the published evidence has not been completed. We therefore conducted a systematic review on the effect of vitamin D on the protein expression and secretion of inflammatory markers by human-derived immune cells. The review was registered at the International Prospective Register for Systematic Reviews (PROSPERO, Registration number CRD42015023222). A literature search was conducted using Pubmed, Science Direct, Scopus, Web of Science and Medline. The search strategy used the following search terms: Vitamin D or cholecalciferol or 1,25-dihydroxyvitamin or 25-hydroxy-Vitamin D and Inflam* or cytokine* and supplement* or cell*. These terms were searched in the abstract, title and keywords. Inclusion criteria for study selection consisted of human-derived immune cell lines or cellular studies where PBMCs were obtained from humans, reported in the English language, and within the time period of 2000 to 2015. The selection protocol was mapped according to PRISMA guidelines. Twenty three studies (7 cell line and 16 PBMCs studies) met our criteria. All studies selected except one used the active metabolite 1,25(OH)2, with one study using cholecalciferol and two studies also using 25(OH)D. Four out of seven cell line studies showed an anti-inflammatory effect where suppression of key markers such as macrophage chemotactic protein 1, interleukin 6 and interleukin 8 were observed. Fourteen of sixteen PBMC studies also showed a similar anti-inflammatory effect based on common inflammatory endpoints. Mechanisms for such effects included decreased protein expression of toll-like receptor-2 and toll-like receptor-4; lower levels of phosphorylated p38 and p42/42; reduced expression of phosphorylated signal transducer and activator of transcription 5 and decreased reactive oxygen species. This review demonstrates that an anti-inflammatory effect of vitamin D is a consistent observation in studies of cell lines and human derived PBMCs.

Conflict of interest statement

Competing Interests: The authors have declared that no competing interests exist.

Figures

Fig 1. PRISMA flow diagram depicting the systematic study selection process.

PBMC, peripheral blood mononuclear cells.

Fig 2. Overview of VDR-mediated regulation of cytokine transcription, production and secretion in immune cells.

Interaction of VD3 and VDR leads to anti-inflammatory effects through negative regulation of NFκB and STAT1/5-mediated signalling. This results in decreased transcription of TNF-α, IL-6, MCP1 and IL-12β. VDR activation promotes increased intracellular glutathione levels that partially or fully attenuates excessive ROS production (ROS can activate pro-inflammatory NFκB signalling). Activated VDR regulates transcription of IL-2 and IL-10 through epigenetic and conformational changes in the promoter region of these genes. VDR association with the promoter region occurs in a cyclic fashion, which leads to initial gene suppression, followed by upregulation of IL-2 and IL-10 expression after 48 hours. Pro-inflammatory effects of VD3 were reported and suggested to be linked to increased IL-1β production possibly related to increased ERK1/2 phosphorylation and the transcription factor CEBPβ. The VDR is believed to modulate pro-inflammatory TLR expression both positively and negatively, but the mechanisms are unknown. Plasma membrane associated VDR may induce rapid effects through non-genomic pathways such as modulation of intracellular calcium levels, parathyroid hormone G-protein coupled or other second messenger systems. Non-genomic pathways may cooperate with genomic pathways to influence gene expression. CCAAT/enhancer binding protein beta (CEBPβ), extracellular signal-regulated kinase1/2 (ERK1/2), janus kinase (JAK), monocyte chemotatic protein1 (MCP-1), nuclear factor kappa light chain enhancer of activated B cells (NFκB), mitogen activated protein kinase (p38 MAPK), retinoid X receptor (RXR), reactive oxygen species (ROS), signal transducer and activator of transcription1/5 (STAT1/5), toll-like receptor-2/4 (TLR2/4), tumour necrosis factor alpha (TNF-α), vitamin D3 (VD3), vitamin D receptor (VDR).