It has been also shown that the accumulation of NK cells in CNS is CX3CL1-mediated process [21, 54]. Investigation on this pathway in AD could reveal new insight in disease pathogenesis. However, it should be noted that these results are related to MS and its experimental models that have immunopathologic features similar but not the same to AD. On the other side, there is little data regarding the protective or pathogenic mechanisms of NK cells in autoimmune neuroinflammatory diseases. It has been suggested that NK cells may stimulate autoreactive TH1cells
by IFN-γ secretion [55, 56]. It has been also supposed that NK cells may exert their protective function through direct lysing of dendritic cells and TH1cells or through secretion of immunoregulatory cytokines such MI-503 molecular weight as IL-10 and TGF-β in autoimmune diseases [57, 58]. What factors assign the pathogenic or protective behaviour of NK cells in various neurologic autoimmune diseases is still elusive. However, we think that the microenvironment status in which NK cells are involved could be an important factor for exerting their role as pathogenic and/or protective cells. Regarding the data provided in AD, we can suppose several environmental factors in which NK cells may be managed for exerting different functions. For example,
IL-12 that is produced by activated blood monocytes, macrophages and glial cells can stimulate NK cells for IFN-γ secretion and triggers the TH1 response in the acute phase Selleck PF-01367338 of AD . Interestingly, a positive correlation has been recently reported between IL-12 and T cell levels in CSF of AD patients . Moreover, NK cells expressing
CD4 can migrate towards the CD4-specific chemotactic factor IL-16 . It should Tacrolimus (FK506) be noted that IL-16 is a growth factor for resting CD4+ cells that stimulates the secretion of inflammatory cytokines, such as IL-1β, IL-6 and TNF-α. Moreover, it can increase intracellular Ca+ or inositol-(1,4,5)-triphosphatase and translocation of the PKC . Surprisingly, the signalling pathway that regulates NK lytic function induces activation of PKC and MAPK . Additionally, the recent studies have demonstrated the high levels of IL-16, IL-18 and TGF-β1 mRNA expression in monocyte-macrophages of the peripheral blood of AD patients which are correlated with disease progression in AD patients . IL-18 is a member of the IL-1 family that is expressed by macrophages and DCs and it can induce secretion of TH1 cytokines, which it synergistically acts with IL-12. It is reported that, IL-18 and IL-18 receptor mRNA expression have been observed in the brain of rats . Increase in TGF-β levels was also reported in AD . On the other side, NK cells can be as a source of both latent and active TGF-β . IL-2 can upregulate the production of active TGF-β . The combination of IL-2 and TNF-α has additive effects on TGF-β .