(HEPATOLOGY 2012) Interleukin-33 (IL-33) or IL-1F11 is a recently described member of the IL-1 cytokine family which includes IL-1α, IL-1β, and IL-18.1 IL-33 is widely expressed in various tissues and the cellular sources of IL-33 are mostly endothelial and epithelial cells, as well as smooth muscle cells, keratinocytes, astrocytes, adipocytes, fibroblasts, monocytes, macrophages, hepatic and pancreatic stellate

cells, and hepatocytes.2-5 Once released from the cells, IL-33 mediates its cytokine functions by interacting with its specific heterodimeric receptor comprising ST2 (IL-1 receptor-like 1) and IL-1RAcP (IL-1 receptor accessory protein) in an MAPK Inhibitor Library autocrine or paracrine manner.6, 7 IL-33 targets cells of the immune system mainly by way of the ST2 receptor. The ST2 is expressed by T helper 2 (Th2)-cells, basophils, eosinophils, natural killer (NK) cells, natural killer

T (NKT) cells, and dendritic cells. Functionally, IL-33 can act as a chemoattractant for Th2 lymphocytes and induce various proinflammatory cytokines or inflammatory mediators.5, 8 The expression of IL-33 has been clearly selleck products associated with many acute and chronic inflammatory diseases including arthritis, asthma, lung inflammation, allergy, Crohn’s disease, ulcerative colitis, sepsis, anaphylactic shock, and hepatitis.2, 3, 9 Recently, we and others have shown that the IL-33/ST2 axis could play an important Rucaparib nmr role in acute and chronic liver diseases.2, 3, 10 Surprisingly, we found that IL-33 is strongly expressed in hepatocytes and demonstrated that

NKT cells were responsible for regulating IL-33 in hepatocytes during concanavalin A (ConA)-induced acute hepatitis.2 Pretreatment of WT mice with recombinant IL-33 prevents the severity of ConA-induced liver damage by recruiting regulatory T-cells and CD4+ T-cells into the liver.10 However, the molecular mechanisms that trigger nuclear IL-33 expression in hepatocytes remain unknown. The administration of ConA in mice provides an experimental model of T-cell-mediated liver injury, which resembles viral or autoimmune hepatitis in humans.11, 12 In the ConA model, the cytotoxic effector molecules and their receptors like tumor necrosis factor alpha (TNFα), perforin-granzyme, FasL/Fas, and tumor necrosis factor related apoptosis inducing ligand (TRAIL)/DR5 play a crucial role for hepatitis development as well as hepatocyte cell death.13-25 Indeed, TRAIL and DR5 expression increase and liver injury is suppressed in TRAIL−/− mice or after blockage of the DR5 receptor, which suggests a critical role of TRAIL/DR5 in the pathophysiology of ConA-induced acute hepatitis.23, 24 In the present study, we aimed to better characterize the expression of IL-33 during acute hepatitis by using wildtype (WT), perforin−/−, TRAIL−/−, and CD1d−/− mice as well as in primary murine hepatocytes.