Interleukin-1 Family Cytokines in Liver Diseases

Figure 4

Mechanisms for IL-1-mediated liver diseases. Intake of acetaminophen, alcohol, or perhaps diet induces necroptosis of hepatocytes via activation of RIP3. Ischemia-reperfusion also causes RIP3-mediated hepatocyte necroptosis. Necroptotic hepatocytes release their cellular contents, including IL-1α and DAMPs. DAMPs such as saturated FFAs, which are metabolites of high-calorie diets, and endogenous PAMPs, such as LPS translocated from the gut microbiome, can activate NLRP3 inflammasomes to release IL-1β. In turn, IL-1β and IL-1α exacerbate the liver inflammation and injury. This inflammation-amplifying mechanism is known as “sterile inflammation,” given the absence of exogenous microbes or their PAMP products. In contrast, IL-18 regulates NASH via maintenance of healthy intestinal microbiota. APAP: acetaminophen; ASH: alcoholic induced steatohepatitis; DAMPs: damage-associated molecular patterns; DILI: drug-induced liver injury; I/R: ischemia-reperfusion injury; NASH: nonalcoholic steatohepatitis; NLRP3: NACHT, leucine-rich repeat, and pyrin domain-containing protein-3; PAMPs: pathogen-associated molecular patterns; RIP3: receptor interacting protein kinase-3.