We also now formally demonstrate activation of the inflammasome by Borrelia. When spleen cells of mice lacking IL-1β were stimulated with Borrelia, IL-17 production was significantly diminished, which also raises the hypothesis that the IL-1β is also involved in induction

of Th17 cells by Borrelia spp. IL-17 Palbociclib mw is associated with more severe disease progression in several autoimmune disorders, such as rheumatoid arthritis (RA) or multiple sclerosis 41. In patients diagnosed with RA, elevated levels of IL-17 were found in synovial fluid 42, 43. Since several clinical symptoms between RA and Lyme arthritis are similar, it has been proposed that IL-17 might be involved in the development of Lyme arthritis 10. In line with this hypothesis, it has been demonstrated that blockade of endogenous U0126 cell line IL-17 in IFN-γ-deficient mice results in complete protection against development of arthritis after infection by Borrelia 44. These data

indicate that controlling the IL-17 response by IFN-γ plays an important role in chronic Lyme disease. IL-33 is a member of the IL-1 family and is mainly involved in induction of T-helper 2-like cytokines, such as IL-4 and IL-5 23. Although it was shown that IL-33 is cleaved by caspase-1, the activity of the mature protein has never been assessed. IL-33 can be secreted from cells after caspase-1 stimulation 45, very recent data suggest that IL-33 activity is independent of caspase-1 46, 47. More recently, it was shown that IL-33 can be functionally active and binds to its receptor ST2 without being cleaved by caspase-1, and that this cytokine is more related to IL-1α than to IL-1β or IL-18 48. It was also described that IL-33/ST2 binding results in the regulation of mainly Th2 responses, which is in line with our results. IL-33 seems not to be involved in either IL-17 or IFN-γ production by Borrelia spp. 23. In this study, we also demonstrate that IL-33 does not play a role in the regulation of pro-inflammatory

cytokines such as IL-1β and IL-6 induced after Borrelia exposure. This study demonstrates modulation of IFN-γ/IL-17 responses by Borrelia spp. through mafosfamide inflammasome and caspase-1 activity. These findings are the first to demonstrate the existence of a counter-regulatory mechanism of Th1 versus Th17 cytokines during stimulation with Borrelia spp.. As shown in this study, IL-18 is crucial for the Borrelia-induced IFN-γ production, and IFN-γ has been suggested to be essential for induction of Th1 cells. Th1 cells drive cell-mediated immune responses and support the fight against invading pathogens. Induction of Th1 cells after recognition of Borrelia might be very important in the early immune response against spirochetes.