, [1,25(OH) 2 D 3 ] is the hormonally active form of vitamin D. The genomic mechanism of 1,25(OH) 2 D 3 action involves the direct binding of the 1,25(OH) 2 D 3 activated vitamin D receptor/retinoic X receptor (VDR/RXR) heterodimeric complex to specific DNA sequences. Numerous VDR co-regulatory proteins have been identified, and genome-wide studies have shown that the actions of 1,25(OH) 2 D 3 involve regulation of gene activity at a range of locations many kilobases from the transcription start site. The structure of the liganded VDR/RXR complex was recently characterized using cryoelectron microscopy, X-ray scattering, and hydrogen deuterium exchange. These recent technological advances will result in a more complete understanding of VDR coactivator interactions, thus facilitating cell and gene specific clinical applications. Although the identification of mechanisms mediating VDR-regulated transcription has been one focus of recent research in the field, other topics of fundamental importance include the identification and functional significance of proteins involved in the metabolism of vitamin D. CYP2R1 has been identified as the most important 25-hydroxylase, and a critical role for CYP24A1 in humans was noted in studies showing that inactivating mutations in CYP24A1 are a probable cause of idiopathic infantile hypercalcemia. In addition, studies using knockout and transgenic mice have provided new insight on the physiological role of vitamin D in classical target tissues as well as evidence of extraskeletal effects of 1,25(OH) 2 D 3 including inhibition of cancer progression, effects on the cardiovascular system, and immunomodulatory effects in certain autoimmune diseases. Some of the mechanistic findings in mouse models have also been observed in humans. The identification of similar pathways in humans could lead to the development of new therapies to prevent and treat disease.

No abstract

A new class of inflammatory CD4؉ T cells that produce interleukin-17 (IL-17) (termed Th17) has been identified, which plays a critical role in numerous inflammatory conditions and autoimmune diseases. Interleukin-17A (IL-17A)-producing T cells are a subset of CD4 ϩ T cell lineage, termed Th17, distinct from Th1, Th2, and T regulatory (T reg ) subsets (52). IL-17 is involved in the pathogenesis of autoimmune inflammation and has been implicated in numerous autoimmune diseases, including systemic lupus erythematosus, rheumatoid arthritis, and multiple sclerosis (MS) (10,21,26,41). IL-17 mRNA and protein levels in patients with MS have been shown to be increased in mononuclear cells isolated from blood, in cerebrospinal fluid, and in brain lesions (39,41). IL-17 is also increased in lymphocytes derived from mice with experimental autoimmune encephalomyelitis (EAE; mouse model for multiple sclerosis) (33). In IL-17A knockout (KO) mice, EAE is markedly suppressed, indicating that IL-17 contributes to the development of EAE (33). Although it has been reported that the transcription factors nuclear factor for activated T cells (NFAT), retinoid orphan nuclear receptor ␥t (ROR␥t), and Runt-related transcription factor 1 (Runx1) are important for the T cell receptor (TCR)-mediated transcriptional regulation of IL-17A (24, 29, 38, 74), knowledge of the factors involved in the cellular and molecular regulation of IL-17A remains limited.The principle function of the active form of vitamin D,, is the maintenance of calcium and phosphate homeostasis (13). However, vitamin D has numerous other functions, including downregulation of autoimmunity (7,8,25,55). 1,25(OH) 2 D 3 has been reported to at least partially protect against a number of experimental autoimmune diseases, including EAE (7,8,11,35,40,53). In addition, numerous epidemiological studies have indicated a negative correlation between increased sun exposure, which would result in a higher vitamin D synthetic rate, and diets rich in vitamin D and MS prevalence (34,55,70

Synopsis The biologically active metabolite of vitamin D, 1,25(OH)2D3, affects mineral homeostasis and has numerous other diverse physiological functions including effects on growth of cancer cells and protection against certain immune disorders. This chapter reviews the role of vitamin D hydroxylases in providing a tightly regulated supply of 1,25(OH)2D3. The role of extrarenal 1α(OH)ase in placenta and macrophages is also discussed as well as regulation of the hydroxylases and vitamin D hydroxylases in aging and chronic kidney disease. Understanding specific factors involved in regulating the hydroxylases may lead to the design of drugs that can selectively modulate the hydroxylases. The ability to alter levels of these enzymes would have therapeutic potential for the treatment of various diseases including bone loss disorders and certain immune diseases.