The Anti-Inflammatory Effects of Vitamin D in Tumorigenesis

Abstract

In conjunction with the classical functions of regulating intestinal, bone, and kidney calcium and phosphorus absorption, as well as bone mineralization of vitamin D, the population-based association between low vitamin D status and increased cancer risk is now generally accepted. Inflammation is causally related to oncogenesis. It is widely thought that vitamin D plays an important role in the modulation of the inflammation system by regulating the production of inflammatory cytokines and immune cells, which are crucial for the pathogenesis of many immune-related diseases. Mechanistic studies have shown that vitamin D influences inflammatory processes involved in cancer progression, including cytokines, prostaglandins, MAP kinase phosphatase 5 (MKP5), the nuclear factor kappa B (NF-κB) pathway, and immune cells. Multiple studies have shown that vitamin D has the potential to inhibit tumor development by interfering with the inflammation system. The present review summarizes recent studies of the mechanisms of vitamin D on regulating the inflammation system, which contributes to its potential for cancer prevention and therapy. This review helps answer whether inflammation mediates a causal relationship between vitamin D and tumorigenesis.

Keywords: cytokines; immune cells; inflammation; tumorigenesis; vitamin D.

Figure 1

Vitamin metabolism. Vitamin D is synthesized by UVB radiation in the epidermis of skin or obtained from diet, hydroxylated to form 25(OH)D by CYP2R1 and CYP27A1 in liver, further metabolized by CYP27B1 in kidney to 1,25(OH)2D3 (calcitriol), and binds to the vitamin D receptor (VDR) which then heterodimerizes with retinoid X receptor (RXR). The 1,25(OH)₂D₃-VDR-RXR complex binds to promoter regions (VDREs) of vitamin D-responsive genes to modulate gene expression.

Figure 2

The effects of vitamin D of inflammation in tumorigenesis. These include the following. (1) Regulate the levels of cytokines including IL-6, IL-8, IL-17A, IL-10 and TGF-β; (2) inhibit NF-κB signaling pathway; (3) up-regulate the expression of MAP kinase phosphatase 5; (4) inhibit the prostaglandins pathway via reducing PG receptors (EPs), decreasing COX-2 expression and increasing 15-PGDH expression; (5) inhibit the immune cells via VDR including macrophages, DCs, B cells and T cells. Upward arrows indicate activation, downward arrows indicate inhibition.