[51, 54, 66, 68] In the pathogenesis of ASH and NASH, activated Kupffer cells exert their pathogenic effects predominantly via inflammatory cytokines, such as TNF-α, IL-1β, IL-8, or MCP-1.[51, 53, 69, 70] Although TLR4-dependent mechanisms are involved in upregulation of
inflammatory mediators, IL-1β is specific because it is produced as inactive pro-IL-1β and buy Dinaciclib requires inflammasomes for processing. Caspase-1, the effector component of the inflammasome, cleaves pro-IL-1β into the bioactive IL-1β, which acts in an autocrine/paracrine manner via the Type-I IL-1 receptor (IL-1R1). The activation of IL-1R1 is inhibited by its binding to the IL-1 receptor antagonist (IL-1Ra), a
naturally occurring cytokine whose function is to prevent the biologic response to IL-1. Studies have demonstrated a pathogenic role of IL-1 signaling in the murine model of NASH,[51, 54] upregulation of inflammasome components in the liver and increased serum levels of IL-1Ra in patients with NASH[66, 73] and increased levels of IL-1β in patients with ASH. However, there were no data supporting the causal role of IL-1 signaling in ASH, and there were only limited data on the cellular source and mechanism of IL-1β activation in NASH. In our studies, we observed that inflammasome see more and IL-1β were activated in ASH, as documented by increased expression of inflammasome components NALP3 (NLR family, pyrin domain-containing 3), ASC (apoptosis-associated speck-like protein containing a CARD), and caspase-1 in the livers of alcohol-fed mice, and by
increased activity of liver caspase-1 and elevated levels of cleaved IL-1β in the liver and in the serum. Deficiency of inflammasome components ASC or caspase-1, significantly ameliorated alcohol-induced liver inflammation, steatosis, and damage. Similar protection was observed in mice deficient in IL-1R1 which lack IL-1 signaling, and in mice treated with recombinant IL-1Ra which inhibits IL-1 signaling. Similar to ASH, the of methionine-choline deficient diet (MCD)-based mouse model of NASH demonstrated activation of caspase-1 in the liver and increased levels of cleaved IL-1β in the liver and in the serum after six weeks of treatment.[66, 68] Using the high-fat diet model of NASH, we observed that caspase-1 and IL-1β became activated at a later time point of nine months along with increased inflammation, but not at four weeks when liver pathology was dominated by steatosis only. This finding contrasted with our ASH data which demonstrated that inflammasome activation occurs very early in the course of alcohol treatment. Furthermore, deficiency of caspase-1 significantly ameliorated only liver inflammation induced by the MCD diet but did not alleviate liver damage.