They also found that mice lacking either NLRP3 or the ASC component of the inflammasome were protected against tetrachloride- or thioactamide-induced liver damage 40. Imaeda and co-workers found that IL-1β synthesis in the liver is dependent on TLR9- and NLRP3-mediated pathways 41. They used acetaminophen-induced liver injury and various mouse gene

knockouts to demonstrate that DNA released by the damaged hepatocytes activates the TLR9 pathway to produce pro-IL-1 and IL-18, and that NLRP3 inflammasome components (NLRP3, ASC or caspase-1) are required to produce the mature cytokines. Knockout mice lacking either TLR9 or one of the NLRP3 inflammasome components show reduced synthesis of IL-1β and IL-18, and subsequent reduced mortality and liver injury after acetaminophen treatment. The authors also found that liver injury could be significantly Fulvestrant mouse reduced if the animals were treated with aspirin before or concordantly with acetaminophen. The beneficial effect of aspirin in this case was found to be mainly due to its ability to downregulate pro-IL-1β and pro-IL-18 transcription. These studies confirm that, apart from the direct cytotoxic effects of, for example, acetaminophen, IL-1β- and IL-18-mediated innate immune responses play a significant role in causing liver damage. These cytokines are, therefore, logical targets to be considered when deciding how to best treat acute and chronic liver

damage in the future. The main reservation regarding the potential success of this approach is the reported finding that, under certain circumstances, NLRP3/ASC/caspase-1 complex activation may directly lead to cell death rather than IL-1β production 42; this mechanism may also Compound Library concentration have contributed to liver damage in the experimental animals. Rheumatoid arthritis (RA) was the first major disease in which IL-1 blockade was tested. Anakinra was well tolerated in patients

with active RA, and moderately effective when used as monotherapy, or in combination with methotrexate 43, 44. However, a systematic review, published in 2009, concluded that the through utility of anakinra for the treatment of RA is likely to be limited; only modest improvements have been reported, compared with other biological medications, such as anti-TNF therapy 45. It seems plausible therefore that unlike TNF and IL-6, IL-1β is not pivotal in the hierarchy of cytokines orchestrating the marked immunological perturbations in autoimmune conditions such as RA. Anti-IL-1β therapy has had a major impact on the treatment of a number of autoinflammatory diseases, particularly the HPF, although it would appear be less effective in treatment of autoimmune disease. However, increasing knowledge of the function of the NLRP3 inflammasome in other complex disorders is suggesting that a niche will also be found for this approach in a subset of these disorders. G. Cook is supported by Yorkshire Cancer Research, S. Savic by the NIHR-Leeds Musculoskeletal Biomedical Research Unit (LMBRU), M.