Extra-renal 25-hydroxyvitamin D3-1α-hydroxylase in human health and disease

Although ectopic expression of 25-hydroxyvitamin D-3-1 alpha-hydroxylase (1 alpha-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 1 alpha-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 1 alpha-OHase activity remains that found in some patients with granulomatous diseases where locally synthesized 1 alpha,25(OH)(2)D-3 has the potential to spill-over into the general circulation. However, immunohistochemistry and mRNA analyses suggest that 1 alpha-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 1 alpha-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. (c) 2006 Published by Elsevier Ltd.