Because the antiproliferative effects on the helper cell populations are more robust than they are on suppressor cells, the net result is relative suppression of the adaptive immune response, with the major suppressive effect at the level of the CYP27B1-hydroxylating activity mediated by the Th2 product IL4 . kidney and the placenta . The overall conclusion drawn from these data was that expression of the in healthy mice is very limited without an additional stimulus. However, more recent work using a chondrocyte-specific knockout of in the mouse resulted in an animal possessing a wide range of bone and growth plate abnormalities  with the opposite phenotype being observed in mice with transgenic over-expression of the in the chondrocyte . It is these kinds of tissue/cell specific gene results that lend credence to the idea that expression of CYP27B1 in other tissues/cells, such as in bone-forming osteoblasts [7,8], is associated with vitamin D function expression, synthesis of 1 1,25(OH)2D and concomitant localized, intracrine, signaling via the vitamin D receptor (VDR) have been proposed for (Z)-SMI-4a other tissues such as the skin , parathyroid glands , prostate gland  and breast . Conclusive evidence for local generation of 1 1,25(OH)2D from 25(OH)D in these tissues has yet to be published but is currently being addressed in tissue specific knockout and transgenic mouse models. Nonetheless, so far in humans quantitative (Z)-SMI-4a expression of the functional gene product to a level that contributes to the circulating concentrations of 1 1,25(OH)2D and acts in an endocrine mode occurs only in disease-activated, tissue macrophages and the placenta. In the former situation production of the vitamin D hormone may be so prolific that the endocrine actions of 1 1,25(OH)2D at the level of the skeleton are sufficient to promote accelerated bone resorption with a pathological increase in the circulating calcium concentration. The placenta, on the other hand, is capable of providing far less hormone to the circulating pool . Along with the maternal kidney, the placenta is capable of contributing to a rise in the serum level of 1,25(OH)2D during pregnancy; the elevated serum 1,25(OH)2D concentration of pregnancy does not lead to a pathological increase of bone resorption . In view of the clear-cut pathophysiological and physiological contributions of the macrophage and placenta, respectively, to a documented increase in the circulating serum 1,25(OH)2D level the following review will feature the placenta and macrophage as bona fide cites for expression of the gene outside (Z)-SMI-4a of the kidney. 1.2 The phylogeny of 1 1,25-(OH)2D function The human genome contains just a little IL7R antibody over 25,000 structural genes. With such a limited repertoire of genes, humans have evolved to use a single structural gene product for functionally distinct purposes. The CYP27B1, the product of a single structural gene, is one such example. As depicted in Table 1, it is proposed that the gene has evolved to produce 1,25(OH)2D for two distinct functions. The more recent function of 1 1,25(OH)2D from phylogenic point of view is that of a circulating endocrine factor, a hormone, designed to guarantee a readily accessible source of calcium and phosphate to the host for skeletal maintenance. The 1,25(OH)2D hormone is made almost exclusively by the CYP27B1 in the proximal tubular epithelial (PTE) cell at the human kidney. Like other hormones, it is designed to find its way back into the general circulation and to act at a distance from its site of synthesis. The production of 1 1,25(OH)2D in the proximal tubular epithelial cell of the kidney is regulated by other hormones, namely PTH and FGF23, which up- and down-regulate expression of the gene, respectively . Importantly, when the concentration of substrate 25-hydroxyvitamin D (25OHD) is diminished, as is seen in states of vitamin D deficiency, production of 1 1,25(OH)2D in the healthy kidney increases. Table 1 Proposed, evolutionarily distinct functions of 1 1,25-dihydroxyvitamin D. is regulated by other inflammatory cytokines (e.g., IFN- and IL15; ). At least partially owing to the transcription of an amino-terminally truncated, enzymatically-defunct CYP24A1 (24-hydroxylase; ), synthesis of 1 1,25(OH)2D the cytokine and the activity of the CYP27B1 in the inflammatory cell is substrate dependent, such that the extracellular concentration of available, free 25OHD is the major determinant of how much 1,25(OH)2D will be produced by that cell. In other words, when the serum 25OHD level goes down the inflammatory cell 1,25(OH)2D synthetic rate will also fall . Open in a separate window Figure 1 Classes of lymphocytes designed to help (left; Th1, Th17 and immunoglobulin-producing.
Because the antiproliferative effects on the helper cell populations are more robust than they are on suppressor cells, the net result is relative suppression of the adaptive immune response, with the major suppressive effect at the level of the CYP27B1-hydroxylating activity mediated by the Th2 product IL4 
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