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T CELLS MODULATE VDR EXPRESSION IN OTHER IMMUNE CELLS
A recent study by Edfeldt et al. revealed that VDR expression is not only modulated on a single cell level. Their study showed that VDR expression of innate immune cells could be regulated by nearby T cells (Edfeldt et al., 2010). In innate immunity, pathogen-induced signaling through Toll-like-receptors on human monocytes and macrophages up-regulate the expression of VDR. This in turn, leads to VDR-induced expression of the antimicrobial peptide cathelicidin resulting in killing of microbes (Liu et al., 2006). VDR-induced cathelicidin expression by human monocytes was shown to be adjusted by cytokines produced by T cells. By modulating the level ofVDR and the amount ofVDR-ligand available by adjusting the CYP27B1 level, the T cell cytokine IFN-y increases cathelicidin expression and IL-4 attenuates cathelicidin expression (Edfeldt et al., 2010). This example illustrates how interplay between innate and adaptive immunity cooperates to mount an appropriate response to infection through regulation of the VDR-system.
This review indicates that VDR expression and activity are important for all stages of a T cells life, ranging from development to differentiation and elicitation of effector functions. In concordance, VDR expression and activity are associated with immunity against certain infections and with the prevalence ofsome autoimmune diseases. In animal models 1,25(OH)2D3 has been shown to prevent development of autoimmune diseases. This includes experimental autoimmune encephalomyelitis (EAE), the animal model for MS (Mayne et al., 2011). EAE studies performed in VDR-KO animals (Bouillon et al., 2008) or in animals with a dysfunctional VDR (Mayne et al., 2011) illustrates the requirement of a functional VDR in 1,25(OH)2D3 mediated EAE-inhibition. Furthermore, a study by Hayes and coworkers showed that VDR-gene inactivation selectively in the T cells completely eradicated the ability of 1,25(OH)2D3 to inhibit EAE (Mayne et al., 2011). The biological relevance of low levels of VDR in development of MS was confirmed in a microarray analysis performed by Achiron et al. Here they compared blood mononuclear cells from healthy subjects that later developed MS with healthy subjects that remained MS-free. One of the early disease markers identified turned out to be suppressed VDR expression (Achiron et al., 2010). These observations may not only reflect a change in conventional T cells (e.g., development of more memory T cells that are predisposed to develop into Th1 and Th17 cells as observed in VDR-KO mice (Bruce et al., 2011) but also a reduced development of iNKT cells (as observed in VDR-KO mice, Yu and Cantorna, 2008; Ooi et al., 2012). iNKT cells are negative regulators of EAE (Matsuda et al., 2008) and furthermore, fewer iNKT cells can be found in the blood of MS patients (Araki etal.,2003). Alongthis line Araki etal. (2003) showed that an increase in iNKT cell number is associated with remission from symptoms in MS patients. Altogether, these observations emphasize a role for VDR expression in development and progression of autoimmunity.
Most experiments investigating susceptibility to a given autoimmune disease is, however, based on animal models. The question therefore remains whether these animal models which are executed in a pathogen free environment reflect the real life situation where humans continuously are bombarded with a variety of pathogens. It is slowly becoming apparent that the microbial environment has a greater influence on development of autoimmune diseases than previously anticipated. For example, certain microbes have been shown to slow innate immune defenses by dysregulating the VDR. One mechanism used by the innate immune system to clear a pathogen is VDR-induced production of the antimicrobial peptide cathelicidin which possesses antiviral, antibacterial, and antifungal activity. Therefore, any microbe capable of dysregulating expression of the VDR would enhance its chance for survival (Waterhouse et al., 2009; Proal et al., 2013). Klein and coworkers illustrated in vitro that Epstein-Barr virus (EBV) were able to effectively down-regulate expression of VDR in B cells (Yenamandra et al., 2009), Modlin and coworkers that Mycobacterium leprae inhibits VDR activity through down-regulation of CYP27B1 in monocytes (Liu et al., 2012), Wang and coworkers that Mycobacterium tuberculosis down-regulate expression of VDR in macrophages (Xu et al., 2003), and McElvaney and coworkers that the fungus Aspergillus fumigates secretes a toxin capable of down-regulating VDR in macrophages (Coughlan et al., 2012). This allows pathogens to accumulate in tissue and blood and the weakened innate defense further causes susceptibility to additional infections. As more pathogens are incorporated into this microbiome, people start to show symptoms characteristic of inflammatory and autoimmune diseases. Accumulating evidence now supports the observation that a number of autoimmune diseases can be reversed by restoring VDR function (using the VDR agonist olmesartan) along with antibiotics. This includes rheumatoid arthritis, systemic lupus erythematosis, sarcoidosis, scleroderma, psoriasis, Sjogren's syndrome, autoimmune thyroid disease, and type I and II diabetes mellitus (Waterhouse et al., 2009; Proal et al., 2013). Knowledge of the regulation of VDR abundance and activity in immune cells potentially is of great therapeutic importance, and therapeutic enhancement of VDR should therefore be considered in the clinic today.
Hi, and thanks for sharing. Intracellular 1,25-dihydroxyvitamin D receptor (VDR) is expressed in human skeletal muscle tissue. Studies suggest that circulating 25-hydroxyvitamin D [25(OH)D] interacts with the vitamin D receptor (VDR) to decrease proliferation of tumor cells. Regards.
yes in europe they are actually curing cancer already with gcmaf by vdr activation which is not expressed on skeletal muscle tissue only but on immune system cells in particular and many others
patients on human trials with 3 months to live are getting regression of tumors from 44% to 58% in 2 weeks...this will be probably the follow up of front page gcmaf article of oncology immunology of august 2013 and maybe reported already in the gcmaf international conference in dubai 5-67 dec which will update on autism, CFS and neruological diseases too
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