Vitamin D and the Lung Mechanisms and Disease Associations
Vitamin D deficiency is a worldwide problem and many associations with diseases are being discovered. Recently, there has been an interest in the role that vitamin D plays in the inception and progression of lung disease. Vitamin D and the Lung: Mechanism
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Vitamin D and Regulatory T Cells Zoë Urry, Sarah Dimeloe, and Catherine M. Hawrylowicz
Abstract Epidemiological studies highlight the rising prevalence of vitamin D deficiency and insufficiency and its association with poor respiratory health, including asthmatic disease. These and further studies have increased interest in the immunomodulatory properties of vitamin D beyond its well-defined role in bone health and calcium homeostasis. The vitamin D receptor (VDR) is ubiquitously expressed in cells of the immune system including activated T cells. This chapter discusses recent evidence that vitamin D promotes a specific T cell subset, namely regulatory T cells, which have a potentially vital role in the regulation of inappropriate disease-causing immune responses in the lung. Emerging clinical data on the capacity of vitamin D to promote both IL-10- and FoxP3-expressing cells are also discussed. Keywords Regulatory T cells • Interleukin-10 • FoxP3 • Vitamin D • Tolerance • Asthma
Introduction The active form of vitamin D, 1a,25-dihydroxyvitamin D3 (1a25VitD3), mediates its biological actions through the vitamin D receptor (VDR), a ligand-dependent transcription factor and member of the nuclear steroid/thyroid hormone receptor superfamily. Within the haematopoietic system, VDR is expressed in various cell types including macrophages, dendritic cells and activated T and B lymphocytes.
Z. Urry • S. Dimeloe • C.M. Hawrylowicz (*) Medical Research Council and Asthma United Kingdom Centre in Allergic Mechanisms of Asthma, King’s College London, London, UK Kings College London, Guy’s Hospital, 5th Floor Tower Wing, London, SE 9RT, UK e-mail: [email protected]; [email protected]; [email protected] A.A. Litonjua (ed.), Vitamin D and the Lung: Mechanisms and Disease Associations, Respiratory Medicine, DOI 10.1007/978-1-61779-888-7_5, © Springer Science+Business Media, LLC 2012
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Of note, VDR expression increases in T cells upon T cell receptor (TCR) stimulation in a ligand-independent manner [1]. Local production of the key rate-limiting enzyme 1a-hydroxylase (CYP27B1) determines cellular expression levels of 1a25VitD3. This enzyme is expressed by proximal renal tubular cells, which represent the major source of serum 1a25VitD3 [2]. Extra-renal sites of 1a25VitD3 synthesis have been described in a range of cell types such as macrophages [3], including pulmonary alveolar macrophages [4], epithelial cells and monocyte-derived dendritic cells (DCs) [5]. T cell-derived cytokines, such as IFN-g and IL-4, have also been shown to regulate the metabolism of 1a25VitD3 by modulating the expression levels of the key metabolic enzymes [6]. Local levels of 1a25VitD3 are also tightly regulated; CYP24, the enzyme that degrades 1a25VitD3 into an inactive metabolite, is highly upregulated upon receptor– ligand interaction. DCs are essential for the activation of naïve T cells and determine the nature and magnitude of T cell responses. The capacity of 1a25VitD3 to inhibit the maturation, cytok
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