The role of AR in androgen-dependent prostate carcinomas has been well established over years, and recently confirmed using an inducible AR-shRNA lentiviral

ctive immune responses. Calcium is a universal and important ion that plays an obligatory role in the regulation of a number of cellular processes. Calcium concentrations and oscillations govern the selective activation and inactivation of transcription buy Tedizolid (phosphate) factors. In most cells, a typical calcium response occurs in two phases. The initial response is the depletion of intracellular stores from the endoplasmic reticulum. This is followed by the activation of store operated 16483784 calcium channels that leads to a sustained increase in intracellular calcium concentrations. This second phase of calcium influx is either via calcium release calcium activated channels or via Voltage Gated Calcium Channels or both. The VGCC consist of a transmembrane alpha subunit along with a cytoplasmic beta subunit that mediates signal transduction, with the gamma and delta subunits completing the core complex. Several intracellular proteins and adaptors show close associations with VGCC subunits and regulate various cellular processes. Calcium plays a determinant role in the generation of proinflammatory responses and also regulates the survival of mycobacteria in macrophages. Calcium dependent phagosome maturation involves mycobacterial inhibition of sphingosine kinase that directly contributes to survival of M. tuberculosis within human macrophages. In addition, tuberculosis toxin has been shown to inhibit phagosome maturation that involves the calmodulinPI3K hVPS34 cascade. Further, L-type VGCC has been shown to play major roles in regulating calcium homeostasis in lysosomal storage disease and in Legionella pneumophila infection. We had earlier shown that several M. tuberculosis antigens including culture filtrate protein -10 induce the differentiation and maturation of DCs,. CFP-10 differentiated DCs are phenotypically and morphologically similar to DCs differentiated conventionally with GM-CSF. However, functional characterization showed that, unlike GM-CSF-DCs that induce pro-inflammatory responses, CFP10-DCs induce suppressor responses. Further, Ca Channels and Mycobacteria CFP10-DCs mount poor oxidative burst that results in increased bacterial burden. Supplementing calcium results in increased oxidative burst and reduces bacterial loads. In addition, we recently showed that mycobacteria infected CFP10-DCs show reduced secretion of pro-inflammatory chemokines and cytokines. Conditioning CFP10-DCs with either RANTES & IP-10 or with IL-12 & IFN-c results in increased mobilization of intracellular calcium and the induction of pro-inflammatory responses. This in turn leads to increased clearance of established M. tuberculosis infection in mice which was better than that observed with drug treatment. Since calcium played an important role in our experiments and as the role of VGCC in mediating calcium mobilization during M. 16483784 tuberculosis infection has not been investigated in detail, we therefore, investigated the roles of L-type and R-type VGCC during M. tuberculosis infection. Since CFP10-DCs and GM-CSFDCs share phenotypic similarities ) but differed in their functional outcomes, we carried out parallel experiments with both DCs. This approach not only brings out mechanistic differences between the two DCs but also highlights the functional relevance of DC differentiation by M. tuberculosis antigens such as CFP-10. Our data show that inhibiting L-type and R-type VGCC in DCs, macrophages and PBMCs increases calcium influx. This results in enhanced expression of p

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