The Journal of Steroid Biochemistry and Molecular Biology
Immunoregulation by 1,25-dihydroxyvitamin D3: Basic concepts
Section snippets
Introduction: 1,25-dihydroxyvitamin D3
1,25-Dihydroxyvitamin D3 (1,25(OH)2D3), originally described as an essential hormone for bone and mineral homeostasis, is the biologically active form of the secosteroid Vitamin D3. Although Vitamin D3 can be derived from nutrition (with as major dietary sources fortified dairy products, fatty fish and fish liver oils), the main supply of Vitamin D3 is obtained through photosynthesis in the skin. Exposure of skin to ultraviolet (UV) light (270–300 nm) catalyzes the first step in the Vitamin D3
1,25(OH)2D3 and the immune system: receptors and metabolism
The discovery that the VDR is constitutively expressed by antigen-presenting cells (APCs) such as macrophages and dendritic cells (DCs) and inducibly expressed by lymphocytes following activation suggests a role for 1,25(OH)2D3 in the immune system [5]. Moreover, the enzyme responsible for the final and rate limiting hydroxylation step in the synthesis of 1,25(OH)2D3, 25(OH)D3-1-α-hydroxylase, is expressed by activated macrophages [6] making them able to synthesize and secrete 1,25(OH)2D3 in a
T lymphocytes
After the discovery of VDR expression in most cells of the immune system, a direct effect of 1,25(OH)2D3 on T lymphocytes was shown. Antigen- or lectin-stimulated human and murine T lymphocyte proliferation, cytokine secretion and cell cycle progression from G1a to G1b are inhibited by in vitro addition of 1,25(OH)2D3. The transcription of several key cytokines of T helper (Th)1 lymphocytes, such as IFN-γ and interleukin (IL)-2, is a direct target of 1,25(OH)2D3. By inhibiting IFN-γ
Molecular pathways of 1,25(OH)2D3-mediated immune regulation
Next to the classical mechanism of action of 1,25(OH)2D3, through binding of the ligand-activated transcription factor VDR to VDREs within the promoter region of 1,25(OH)2D3-responsive genes and thus eventually regulating the transcription rate of these genes, there is abundant evidence that the regulation of the transcription of many cytokine genes by 1,25(OH)2D3 results indirectly from modulation of other intracellular signaling pathways. In activated T lymphocytes 1,25(OH)2D3-mediated
In vivo immunomodulatory potential of 1,25(OH)2D3 and its analogs
The fact that 1,25(OH)2D3 influences the immune system, not merely by suppression, but by immune modulation through induction of immune shifts and regulator cells, makes this compound very appealing for clinical use, especially in the treatment and prevention of autoimmune diseases and in the prevention of graft rejection. The major drawback in the widespread clinical application of 1,25(OH)2D3 for its immunomodulatory effects, are the dose-limiting side effects including hypercalcemia,
Effects of Vitamin D deficiency on the immune system
Next to the pharmacological effects of 1,25(OH)2D3 in the immune system, several data point towards a possible physiological immune function of 1,25(OH)2D3, suggesting that Vitamin D deficiency could lead to immune malfunctioning. Subjects with severe Vitamin D deficiency are abnormally susceptible to infections such as tuberculosis [55]. Different studies provide evidence for defects in macrophage functions, such as chemotaxis, phagocytosis and the production of proinflammatory cytokines, in
Conclusions
The widespread presence of VDR in the immune system and the regulated expression of 1-α-hydroxylase by specific immune signals suggest a paracrine immunomodulatory role for 1,25(OH)2D3. Indeed, 1,25(OH)2D3 has pleiotropic activities in the immune system (summarized in Fig. 1). Strikingly, 1,25(OH)2D3 uses several different molecular mechanisms to regulate cytokine expression, either directly targeting transcription initiation and regulation or indirectly interfering with other intracellular
Acknowledgements
The authors would like to thank the Belgian federal government, the Katholieke Universiteit Leuven (KUL), the European Community (EU), the Juvenile Diabetes Research Foundation (JDRF) and the Flemish Research Foundation (FWO) for support.
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