Caspase-1 regulates the inflammatory process leading to autoimmune demyelination

T cell-mediated inflammation is considered to play a key role in the pathog enic mechanisms sustaining multiple sclerosis (MS), Caspase-1, formerly des ignated IL-1 beta-converting enzyme, is crucially involved in immune-mediat ed inflammation because of its pivotal role in regulating the cellular expo rt of IL-1 beta and IL-18. We studied the role of caspase-1 in experimental autoimmune encephalomyelitis (EAE), the animal model for MS. Caspase-1 is transcriptionally induced during EAE, and its levels correlate with the cli nical course and transcription rate of proinflammatory cytolkines such as T NF-alpha, IL-1 beta, IFN-gamma and IL-6, A reduction of EAE incidence and s everity is observed in caspase-1-deficient mice, depending on the immunogen icity and on the amount of the encephalitogenic myelin oligodendrocyte glyc oprotein (MOG) peptide used. In caspase-1-deficient mice, reduced EAE incid ence correlates with defective development of anti-MOG IFN-gamma-producing Th1 cells. Finally, pharmacological blockade of caspase-1 in Biozzi AB/H mi ce, immunized with spinal cord homogenate or MOG(35-55) peptide, by the cas pase-1-inhibitor Z-Val-Ala-DL-Asp-fluoromethylketone, significantly reduces EAE incidence in a preventive but not in a therapeutic protocol. These res ults indicate that caspase-1 plays an important role in the early st:age of the immune-mediated inflammatory process leading to EAE, thus representing a possible therapeutic target in the acute phase of relapsing remitting MS .