These results suggest that both MDR1 and MRPs are involved in DC maturation under LPS and hypoxia. In fact, our results under hypoxia point to a possible downstream mechanistic pathway via hypoxia-induced
expression of HIF-1α. Interestingly, HIF-1α achieved similar values in hypoxia-DCs AZD1152HQPA under both ABC transporter (MDR1 and MRPs) inhibitors to those under hypoxia alone. These findings are in agreement with recent studies in cancer therapy which argue for the contribution of HIF-1α in drug resistance, as HIF-1α is able to activate MDR1 [33]. Currently, it is well known that DCs are a bridge between innate and adaptative immunological responses and that LPS and hypoxia are involved in DC stimulation, but the role of ABC transporters in this context has been not explored [34]. Also, this link between hypoxia and LPS-DCs and ABC transporters DNA Damage inhibitor may be inhibited by some of the most potent immunosuppressive drugs such as cyclosporin, tacrolimus and sirolimus, and this suggests an excellent target for preventing ischaemia-derived inflammation mediated by innate immunity. As described previously, hypoxia is able to increase the release of proinflammatory cytokines and the expression of co-stimulatory molecules by murine and human DCs,
thus enhancing their potential to induce allogeneic lymphocyte proliferation [8, 26]. Hypoxia- and LPS-matured DCs induced significantly higher T cell proliferation than immature untreated DCs, achieving different degrees of T cell proliferation depending on the stimuli. Interestingly, when different subpopulations were assessed, CD8 lymphocyte proliferation was up-regulated remarkably in DCs treated with LPS, while the proliferation of B lymphocytes was higher under hypoxia. Recently it has been reported that plamacytoid DCs are able to induce B lymphocyte proliferation, which lends support to our findings [35]. DCs differentiated in the presence of MDR1 and MRP inhibitors reduced alloimmune T cell proliferation
twofold. Furthermore, ABC transporter inhibitors PI3K inhibitor showed different profiles of lymphocyte proliferation inhibition depending on DC maturation stimuli. Thus, inhibiting ABC transporters could be an effective approach to reducing the stimulatory capacity of DC, thereby decreasing lymphocyte proliferation. DCs are usually exposed to diverse pathological and physiological conditions. In fact, LPS and hypoxia are some of the possible in-vitro stimuli that can simulate the different environments that arise in wide-ranging types of cytokines that may trigger assorted inflammatory processes. However, the effects of these stimuli on phenotype differentiation patterns of DC and of the cytokine prompt cascade remain unclear [36, 37]. In our study, we showed that lymphocytes exposed to LPS-DCs generated higher levels of proinflammatory cytokines (IL-2, IL-6, IL-10, IFN-γ and TNF-α), balanced mainly to the Th1 response.