Macrophages Control the Bioavailability of Vitamin D and Vitamin D-Regulated T Cell Responses

Abstract

The active form of vitamin D3 (1,25(OH)2D3) has a great impact on T cell effector function. Thus, 1,25(OH)2D3 promotes T helper 2 (Th2) and regulatory T (Treg) cell function and concomitantly inhibits Th1 and Th17 cell function. Thus, it is believed that vitamin D exerts anti-inflammatory effects. However, vitamin D binding protein (DBP) strongly binds both 1,25(OH)2D3 and the precursor 25(OH)D3, leaving only a minor fraction of vitamin D in the free, bioavailable form. Accordingly, DBP in physiological concentrations would be expected to block the effect of vitamin D on T cells and dendritic cells. In the present study, we show that pro-inflammatory, monocyte-derived M1 macrophages express very high levels of the 25(OH)D-1α-hydroxylase CYP27B1 that enables them to convert 25(OH)D3 into 1,25(OH)2D3 even in the presence of physiological concentrations of DBP. Co-cultivation of M1 macrophages with T cells allows them to overcome the sequestering of 25(OH)D3 by DBP and to produce sufficient levels of 1,25(OH)2D3 to affect T cell effector function. This study suggests that in highly inflammatory conditions, M1 macrophages can produce sufficient levels of 1,25(OH)2D3 to modify T cell responses and thereby reduce T cell-mediated inflammation via a vitamin D-mediated negative feed-back loop.

Effects of vitamin D on thyroid autoimmunity markers in Hashimoto’s thyroiditis: systematic review and meta-analysis

“…30 1,25 (OH) 2 D 3 down-regulates the expression of the major histocompatibility complex class II and stimulating molecules (CD40, CD80, CD86), increases the production of interleukin (IL)-10 and reduces the secretion of IL-12, thus repressing the Th 1 cell immune response. 31 In contrast, 1,25(OH) 2 D 3 inhibits plasma cell generation, memory cell formation and subsequent secretion of immunoglobulin (Ig)G and IgM by activated B cells. 32 Vitamin D also regulates regulatory B (B reg ) cells involved in immunological tolerance by producing IL-10, IL-35 and transforming growth factor-b.…”

Renal replacement therapy in sarcoidosis

“…Depending on the population studied, about 2–63% of sarcoidosis patients show hypercalcemia ( 29 ). Elevated levels of serum calcium are probably due to overproduction of activated polarized macrophages expressing very high levels of the 25(OH)D-1α-hydroxylase that convert 25(OH)D into 1,25(OH) 2 D 3 ( 30 ). Mild hypercalcemia (<11.5 mg/dl) is often asymptomatic or may be associated with aspecific gastrointestinal troubles.…”

Hypovitaminosis D in Postmenopause

“…Regarding APCs, these pathways trigger the transcription of many cytokines, constituting the third signal, which helps to polarize the stimulated T-cells towards the distinct Th phenotypes. Moreover, these signals are necessary to enhance the transcription of the CYP27B1 enzyme, which stimulates the production of calcitriol in APCs, being released to lymphocytes with the rest of the cytokines as part of the third signal [80]. In this context, the stimulation of 1,25 (OH)2 D3 Together, these phenomena enhance the antimicrobial activity and phagocytosis of APCs without triggering an exaggerated inflammatory response, showing the undoubted capacity of immunomodulation that vitamin D possesses (Figure 5) [77][78][79][80][81].…”