Extra-renal 25-hydroxyvitamin D3-1α-hydroxylase in human health and disease |
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Authors: | Martin Hewison Fiona Burke Katie N. Evans David A. Lammas David M. Sansom Philip Liu Robert L. Modlin John S. Adams |
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Affiliation: | aBurns and Allen Research Institute, Division of Endocrinology, Cedars-Sinai Medical Center and David Geffen School of Medicine at UCLA, Los Angeles, CA 90048, USA;bDivision of Immunity and Infection, Institute of Biomedical Research, The University of Birmingham Medical School, Birmingham B15 2TT, UK;cDepartment of Microbiology, Immunology and Molecular Genetics, David Geffen School of Medicine at UCLA, Los Angeles, CA 90095, USA |
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Abstract: | Although ectopic expression of 25-hydroxyvitamin D3-1α-hydroxylase (1α-OHase) has been recognized for many years, the precise function of this enzyme outside the kidney remains open to debate. Three specific aspects of extra-renal 1α-OHase have attracted most attention: (i) expression and regulation in non-classical tissues during normal physiology; (ii) effects on the immune system and inflammatory disease; (iii) expression and function in tumors. The most well-recognized manifestation of extra-renal 1α-OHase activity remains that found in some patients with granulomatous diseases where locally synthesized 1α,25(OH)2D3 has the potential to spill-over into the general circulation. However, immunohistochemistry and mRNA analyses suggest that 1α-OHase is also expressed by a variety of normal human tissues including the gastrointestinal tract, skin, vasculature and placenta. This has promoted the idea that autocrine/paracrine synthesis of 1,25(OH)2D3 contributes to normal physiology, particularly in mediating the potent effects of vitamin D on innate (macrophage) and acquired (dendritic cell) immunity. We have assessed the capacity for synthesis of 1,25(OH)2D3 in these cells and the functional significance of autocrine responses to 1α-hydroxylase. Data suggest that local synthesis of 1,25(OH)2D3 may be a preferred mode of response to antigenic challenge in many tissues. |
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Keywords: | Vitamin D Extra-renal 1α -Hydroxylase 24-Hydroxylase Granulomatous Macrophage Dendritic cell Crohn's disease Tuberculosis Cancer |
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