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The NFAT family of transcription factors plays a central role in the regulation of cytokine gene expression during the immune response. NFAT functions have been extensively explored in lymphocyte activation and differentiation, but the involvement of NFAT proteins in dendritic cells (DCs) is still not well known. Here, we investigated the role of the NFAT1 transcription factor in murine DCs. Initially, we demonstrated by western blot that the NFAT1 protein is present in splenic DCs and is rapidly activated upon calcium influx. We then used NFAT1-deficient mice (NFAT1-/-) to investigate whether NFAT1 influences the ability of DCs to induce Th differentiation. Our data demonstrated that NFAT1-/- DCs showed an increased capacity to differentiate CD4 T cells to the Th1 phenotype. CD4 cells that were primed in vitro with NFAT1-/- DCs had increased IFN-γ production. The same results were observed when the CD4 cells were primed in vivo through the sensitization of NFAT1-/- mice with ovalbumin. Furthermore, our results demonstrated that the cytokine IL-12 is one of the factors involved in this process because its production is increased in NFAT1-/- mice, and neutralizing anti-IL-12 antibodies almost completely eliminated the IFN-γ production. These results demonstrated that the NFAT1 transcription factor regulates specific functions in DCs that are involved in CD4 differentiation, suggesting that the inhibition of NFAT1 in DCs may be used as a therapy to modulate specific immune responses., (Copyright © 2014 Elsevier GmbH. All rights reserved.)

Breast cancer is the leading cause of deaths in women around the world. Resistance to therapy is the main cause of treatment failure and still little is known about predictive biomarkers for response to systemic therapy. Increasing evidence show that Survivin and XIAP overexpression is closely associated with chemoresistance and poor prognosis in breast cancer. However, their impact on resistance to doxorubicin (dox), a chemotherapeutic agent widely used to treat breast cancer, is poorly understood. Here, we demonstrated that dox inhibited cell viability and induced DNA fragmentation and activation of caspases-3, -7 and -9 in the breast cancer-derived cell lines MCF7 and MDA-MB-231, regardless of different p53 status. Dox exposure resulted in reduction of Survivin and XIAP mRNA and protein levels. However, when we transfected cells with a Survivin-encoding plasmid, we did not observe a cell death-resistant phenotype. XIAP and Survivin silencing, either alone or in combination, had no effect on breast cancer cells sensitivity towards dox. Altogether, we demonstrated that breast cancer cells are sensitive to the chemotherapeutic agent dox irrespective of Survivin and XIAP expression levels. Also, our findings suggest that dox-mediated modulation of Survivin and XIAP might sensitize cells to taxanes when used in a sequential regimen., (Copyright © 2013 Elsevier GmbH. All rights reserved.)

Transcription factors of the NFAT (nuclear factor of activated T cells) family regulate the expression of many genes encoding immunoregulatory cytokines and cell surface proteins during the immune response. The NFAT protein NFAT1 (NFATp) is expressed and functional in T cells, B cells, mast cells, and natural killer cells. Here we report a detailed analysis of the enhanced eosinophil responses of NFAT1-deficient mice, observed in an in vivo model of allergic inflammation. In addition to the pleural eosinophilia described previously, NFAT1-/- mice that have been sensitized with antigen display a significant increase, relative to wild-type mice, in the numbers of eosinophils in bone marrow and peripheral blood. After restimulation with antigen in vitro, antigen-responsive T cells from the draining lymph nodes of NFAT1-/- mice show increased expression of mRNA encoding the Th2 cytokines interleukin-4 (IL-4), IL-5, and IL-13. Consistent with this finding, there is a pronounced increase in the levels of IL-5 and IL-13 in the pleural cavities of sensitized NFAT1-/- mice after allergen challenge in vivo. Furthermore, development of eosinophilia depends on overexpression of IL-4 and IL-5, because it is strongly inhibited by administration of neutralizing antibodies to either of these cytokines. These results indicate that NFAT1-deficient mice are prone to develop a classically allergic phenotype characterized by eosinophilia and increased production of Th2 cytokines. Thus, the presence of NFAT1 might inhibit the allergic response, perhaps by interfering with the development of Th2 immune responses, and the lack or dysfunction of NFAT1 could potentially underlie certain cases of atopic disease.