Vitamin D and inflammatory diseases

Abstract

Beyond its critical function in calcium homeostasis, vitamin D has recently been found to play an important role in the modulation of the immune/inflammation system via regulating the production of inflammatory cytokines and inhibiting the proliferation of proinflammatory cells, both of which are crucial for the pathogenesis of inflammatory diseases. Several studies have associated lower vitamin D status with increased risk and unfavorable outcome of acute infections. Vitamin D supplementation bolsters clinical responses to acute infection. Moreover, chronic inflammatory diseases, such as atherosclerosis-related cardiovascular disease, asthma, inflammatory bowel disease, chronic kidney disease, nonalcoholic fatty liver disease, and others, tend to have lower vitamin D status, which may play a pleiotropic role in the pathogenesis of the diseases. In this article, we review recent epidemiological and interventional studies of vitamin D in various inflammatory diseases. The potential mechanisms of vitamin D in regulating immune/inflammatory responses in inflammatory diseases are also discussed.

Keywords: asthma; atherosclerosis; chronic kidney disease; inflammatory bowel disease.

Figure 1

Schematic representation of the primary mechanisms through which vitamin D regulates macrophage-mediated innate immune response. Notes: vitamin D from sunlight or dietary sources is hydroxylated by the 25-hydroxylase to form its major circulating form – 25(OH)D₃. 25(OH)D₃ is then hydroxylated by 1α-hydroxylase (CYP27B1) to form the hormonal form of vitamin D – 1,25(OH)₂D₃. 1,25(OH)₂D₃ acts to modulate TLR signaling via stimulating SOCS1, inhibiting the phosphorylation of p38 MAPK and activation of NF-κB signaling in human macrophages, which reduces the gene expression and protein release of proinflammatory mediators, such as TNFα, IL-6, and MCP-1, leading to decreased recruitment of monocytes/macrophages and overall inflammation within tissue. In addition, 1,25(OH)₂D₃ acts to increase the production of the antimicrobial peptide cathelicidin and the killing of intracellular mycobacterium tuberculosis (MTB). Abbreviations: LPS, lipopolysaccharide; VDR, vitamin D receptor; VDREs, vitamin D response elements; IL-6, interleukin-6; MAPK, mitogen-activated protein kinase; MCP-1, monocyte chemoattractant protein-1; TLR, toll-like receptor; TNFα, tumor necrosis factor-α.

Figure 2

Schematic representation of the primary mechanisms through which vitamin D-regulated dendritic cells (DCs) and T-lymphocyte function. Notes: vitamin D precursors can be further processed to their active metabolite, 1,25(OH)₂D₃, in DCs and T lymphocytes. In DCs, 1,25(OH)₂D₃ binds to the vitamin D receptor–retinoid X receptor (VDR/RXR) complex in the nucleus, leading to a tolerogenic DC phenotype, characterized by decreased expression of major histocompatibility complex (MHC)-II, CD40, CD80, CD86, enhanced expression of immunoglobulin-like transcript (ILT)-3, and increased secretion of interleukin (IL)-10 and CCL22, which results in the induction of T-regulatory (T_reg) cells. The 1,25(OH)₂D₃ signaling in T-cells is dependent on the stimulation of T-cell antigen-receptor (TCR) signaling. VDR expression can be induced by TCR signaling via the alternative p38 MAPK pathway. 1,25(OH)₂D₃ binds to VDR, leading to inhibition of proinflammatory cytokine expression, including interferon (IFN)-γ, IL-17, and IL-21, and promotion of the development of T_reg cells. Abbreviations: CCL22, chemokine (C-C motif) ligand 22; MAPK, mitogen-activated protein kinase.