THE IMMUNE MODULATING EFFECTS OF VITAMIN D: HOW FAR ARE WE FROM CLINICAL APPLICATIONS?

Vitamin D is one of the key factors in calcium and bone metabolism. Presently more than 30 natural vitamin D metabolites are known, but only la,25- dihydroxyvitamin D3 [1,25(OH)2D3], synthesized under the action of kidney Ia hydroxylase, is considered as being the final active hormonal product (1). The "classical" targets of 1,25(OH)2D3 are the gut, the bone and the kidney, all these organs possessing vitamin D receptors (VDR). l,25(OH)2D3 controls active intestinal absorption of calcium and phosphate, kidney calcium reabsorption, as well as bone metabolism, by acting directly on osteoblasts that possess VDR, and favoring osteoclast differentiation from monocytic precursors (2). In pharmacological doses, 1,25(OH)2D3 becomes toxic, increasing osteoclast formation and bone turnover, and thus leading to toxic effects (rapid bone loss, hypercalcemia, soft tissue calcifications). These toxic effects seem to be cytokine (IL-il) and prostaglandin-mediated (1). 1 ,25(OH) D3 acts through specific intracellular (nuclear) receptors from the same superfaniily as the retinoic acid, steroid and thyroid hormone receptors. Although there is only one vitamin D receptor (VDR) gene located on chromosome 12q13-14, alternate splicing leads to VDR isoforms, of which two most widespread are the f and F isoforms. The longer isoform, f (Mi), has 427 aminoacids, whereas the shorter VDR isoform, F (M4), has 424 aminoacids, lacking 3 aminoacids at the aminoterminal region (3). The VDR binds as a homodimer or as a heterodimer with the retinoid X receptor (RXR), to specific DNA sequences called vitamin D responsive elements (VDRE), situated in the promoter region of various vitamin D responsive genes (4). Coupling of 1,25(OH)2D3 to the VDR increases the affinity of the dimeric receptor complex to the VDRE. As a consequence of this binding, transcriptional activity is modulated through influencing RNA polymerase activity, a process called transactivation (4). Gene transcription is thus up- or down regulated, producing a specific cellular response. Rapid, "non-genomic" actions of l,25(OH)2D3 have also been described in various cell types (5). VDRs are found not only in the classical tissue targets for vitamin D, but also in other cells or tissues that are not involved in the calcium and bone metabolism, such as the brain and brain stem, muscles, thyroid follicular and parafollicular C cells, gonads, pituitary, endocrine pancreas, adrenal gland, prostate, uterus, hair follicle, tumor cells and cells of the immune system (6-9). The presence of the VDR in these tissues suggests that 1,25(OH)2D3 might play other roles than a mere calcium regulator. Indeed, 1 ,25(OH)2D3 has several non-classical or non-calcemic effects, such as inhibition of proliferation and differentiating effects in normal cells (keratinocytes), as well as tumoral cells (colon, prostate, thyroid and breast cancer, or leukemia cells) (9), or modulation of the immune response (9-11). [ABSTRACT FROM AUTHOR]