Potent protein induction

Although l,25(OH)2D3 is a potent inhibitor of Thl-dominated EAE and IFN-y secretion is clearly inhibited in vitro, l,25-(OH)2 D3 failed to suppress Thl cells in vivo using a myelin basic protein induction model of EAE [106]. At the same time, whatsoever, no upregulation of IL-4 transcription was observed in animals protected from EAE through l,25(OH)2D3 [106]. This study speaks against both putative immunoregulatory mechanisms in l,25(OH)2D3 action, inhibition ofThl responses as well as induction of Th2 responses. The immunomodulatory effects of 1,25 (OH)2D3 can therefore not entirely be attributed to and explained by effects on the Thl /Th2 cytokine balance. However, the majority of reports consistently demonstrate that Thl Tcells are relatively more susceptible to l,25(OH)2D3 treatment. This may also explain the clinical efficacy of l,25(OH)2D3 predominantly in the treatment of Thl-mediated diseases as outlined below. 

The mechanism of action of the vitamin D metabolites remains under active investigation. However, calcitriol is well established as the most potent agent with respect to stimulation of intestinal calcium and phosphate transport and bone resorption. Calcitriol appears to act on the intestine both by induction of new protein synthesis (eg, calcium-binding protein and TRPV6, an intestinal calcium channel) and by modulation of calcium flux across the brush border and basolateral membranes by a means that does not require new protein synthesis. The molecular action of calcitriol on bone has received less attention. However, like PTH, calcitriol can induce RANK ligand in osteoblasts and proteins such as osteocalcin, which may regulate the mineralization process. The metabolites 25(OH)D and 24,25(OH)2D are far less... 

The mechanisms by which antitumor-promoters suppress the tumor promotion are not known, but may be due to the following effects (i) inhibition of polyamine metabolism (ii) inhibition of arachidonic acid metabolism (iii) protease inhibition (iv) induction of differentiation (v) inhibition of oncogene expression (vi) inhibition of PKC and (vii) inhibition of oxidative DNA damage [3,6,91]. The polyamine content of cells is correlated to their proliferative, and often, their neoplastic capabilities. A key enzyme in the polyamine biosynthetic pathway, ornithine decarboxylase (ODC), catalyzes the convertion of ornithine to putrescine. Phorbol ester promoters such as TPA cause increased ODC activity and accumulation of polyamines in affected tissues. Diacylglycerol activated PKC, and the potent tumor promoter, TPA, binds to, and activates PKC, in competition with diacylglycerol. PKC stimulation results in phosphorylation of regulatory proteins that affect cell proliferation. Some chemopreventive agents have inhibitory activity towards PKC. Refer to recent review articles for further discussion [3,6,91]. 

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