During the last decades it has become evident that 1,25(OH)2D3, the active form of vitamin D, plays an important role in the immune system, apart from its well-known role in calcium and bone homeostasis. Within the immune system, 1,25(OH)2D3 not only targets both APCs and T cells, which express the vitamin D receptor, but also the different enzymes responsible for activation of vitamin D3 and which are expressed by APCs and/or T cells. Indeed, a recent study convincingly showed 25-hydroxylase expression in DCs, suggesting efficient local activation of the sunlight-generated inactive pro-hormone vitamin D3, for instance in the skin. This finding supported a model in which DCs may play a key role in processing vitamin D3 to program “T-cell homing”.45 Next to this, 1α-hydroxylase is also expressed in monocytes, macrophages, DCs, and T cells. Recent findings point to a complex regulation in which a synergistic induction – upon prolonged exposure – of 1α-hydroxylase by IFNγ and TLR4/CD14 activation is crucial in monocytes/macrophages.77,78 This suggests a potential physiological role in the immune system. In the early phase of inflammation, when only macrophages are involved, 1α-hydroxylase is absent or low. Only upon production of the second necessary signal, IFNγ, by recruitment of other immune cells such as lymphocytes or NK cells, will the activated macrophages induce their 1α-hydroxylase levels and 1,25(OH)2D3 will be produced. This 1,25(OH)2D3 can then perform its well-known immunosuppressive action and shut down the ongoing immune reaction, thus preventing unrestricted immune responses. This complex regulation of 1α-hydroxylase also provides a better understanding of the abnormally high levels of 1,25(OH)2D3 observed in the pleural fluid of patients with different granulomatous diseases, such as sarcoidosis and tuberculosis, which are produced by activated pulmonary alveolar macrophages. From early studies in these diseases, it was clear that IFNγ plays a crucial role in the induction of 1,25(OH)2D3 and, thus, disease-associated hypercalcemia.52,81,82 In addition, it is now clear that IFNγ, although important, is not sufficient alone, since other macrophage activators/differentiators, such as LPS, PMA, or TNF-α, need to be present simultaneously to activate the complex network of signaling pathways necessary for 1α-hydroxylase induction. Adding to this, TLR2/1 triggering, as well as TLR4 activation, is able to induce 1α-hydroxylase in human macrophages, which is paralleled by induction of an antimicrobial response.
Finally, the 1,25(OH)2D3 metabolizing enzyme, 24-hydroxylase, is also expressed by APCs. Intriguingly, although highly induced by active 1,25(OH)2D3 itself, this induction is suppressed in the presence of IFNγ, which again points to an increased production of 1,25(OH)2D3 in situations of inflammation (summarized in Figure 3).
Figure 3. Overview of vitamin D3 homeostasis in the immune system. The presence of both 25-hydroxylase and 1α-hydroxylase has been demonstrated in APCs, enabling them to produce locally active 1,25(OH)2D3. Under steady-state conditions 24-hydroxylase expression is induced by 1,25(OH)2D3 creating a self-regulatory feedback loop and enabling 1,25(OH)2D3 to fulfill its role in maintaining immune balance. In the immune system, and in contrast with the kidney, 1α-hydroxylase is not incorporated in this self regulatory loop. In conditions of infection or inflammation, upregulation of 24-hydroxylase is hampered by interference of IFNγ-induced STAT1α, giving rise to sustained elevation of 1,25(OH)2D3 levels and, thus, sustained antimicrobial activity. Moreover, inflammatory factors, either derived from pathogens or inflammatory mediators produced by the immune system, also stimulate 1α-hydroxylase activity (through multiple intracellular signaling pathways), thereby also contributing to the rise in 1,25(OH)2D3 levels. When inflammation acquires a chronic character, 1,25(OH)2D3 levels may increase such that spillover in the general circulation is unavoidable, with consequent hypercalcemic side effects.
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In conclusion, the presence of both the activating and the metabolizing enzymes by cells of the immune system itself, indicates that 1,25(OH)2D3 can be produced locally in its active form. Moreover, the strict regulation of these enzymes in immune cells is highly suggestive for an autocrine/paracrine role in the immune system, and opens new treatment possibilities. Indeed, it suggests that vitamin D supplementation may be an adequate strategy for the treatment of immune-associated diseases, such as microbial infections and autoimmune diseases.