Extra-renal 25-hydroxyvitamin D3-1alpha-hydroxylase in human health and disease.
Although ectopic expression of 25-hydroxyvitamin D(3)-1alpha-hydroxylase (1alpha-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 1alpha-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 1alpha-OHase activity remains that found in some patients with granulomatous diseases where locally synthesized 1alpha,25(OH)(2)D(3) has the potential to spill-over into the general circulation. However, immunohistochemistry and mRNA analyses suggest that 1alpha-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)(2)D(3) 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)(2)D(3) in these cells and the functional significance of autocrine responses to 1alpha-hydroxylase. Data suggest that local synthesis of 1,25(OH)(2)D(3) may be a preferred mode of response to antigenic challenge in many tissues.
Hewison
Martin
M
Burns and Allen Research Institute, Division of Endocrinology, Cedars-Sinai Medical Center and David Geffen School of Medicine at UCLA, Los Angeles, CA 90048, USA. M.Hewison@bham.ac.uk
Burke
Fiona
F
Evans
Katie N
KN
Lammas
David A
DA
Sansom
David M
DM
Liu
Philip
P
Modlin
Robert L
RL
Adams
John S
JS
D015090:25-Hydroxyvitamin D3 1-alpha-Hydroxylase / Q000378:metabolism*; D002112:Calcifediol / Q000096:biosynthesis; D002478:Cells, Cultured; D003713:Dendritic Cells / Q000201:enzymology; D004194:Disease; D006262:Health; D006801:Humans; D007668:Kidney / Q000201:enzymology*
D015090:25-Hydroxyvitamin D3 1-alpha-Hydroxylase; D002112:Calcifediol