No abstract

Interleukin (IL)-33, a member of the IL-1 cytokine family, positively correlates with acute hepatitis and chronic liver failure in mice and humans. IL-33 is expressed in hepatocytes and is regulated by natural killer T (NKT) cells during concanavalin A (ConA)-induced acute liver injury. Here, we investigated the molecular mechanisms underlying the expression of IL-33 during acute hepatitis. The expression of IL-33 and its regulation by death receptor pathways was investigated after the induction of ConA-acute hepatitis in wildtype (WT), perforin 2/2 , tumor necrosis factor related apoptosis inducing ligand (TRAIL)2/2 , and NKT cell-deficient (CD1d 2/2 ) mice. In addition, we used a model of acute liver injury by administering Jo2/Fas-antibody or D-galactosamine-tumor necrosis factor alpha (TNFa) in WT mice. Finally, the effect of TRAIL on IL-33 expression was assessed in primary cultured murine hepatocytes. We show that IL-33 expression in hepatocytes is partially controlled by perforin during acute liver injury, but not by TNFa or Fas ligand (FasL). Interestingly, the expression of IL-33 in hepatocytes is blocked during ConA-acute hepatitis in TRAIL-deficient mice compared to WT mice. In contrast, administration of recombinant murine TRAIL associated with ConA-priming in CD1d-deficient mice or in vitro stimulation of murine hepatocytes by TRAIL but not by TNFa or Jo2 induced IL-33 expression in hepatocytes. The IL-33-deficient mice exhibited more severe ConA liver injury than WT controls, suggesting a protective effect of IL-33 in ConA-hepatitis. Conclusion: The expression of IL-33 during acute hepatitis is dependent on TRAIL, but not on FasL or TNFa. (HEPATOLOGY 2012;56:2353-2362 I nterleukin-33 (IL-33) or IL-1F11 is a recently described member of the IL-1 cytokine family which includes IL-1a, 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 receptorlike 1) and IL-1RAcP (IL-1 receptor accessory protein) in an 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, Abbreviations: AST, aspartate aminotransferase; ALT, alanine aminotransferase; ConA, concanavalin A; D-GalN, D-galactosamine; FasL, Fas ligand; IL-33, interleukin 33; IL-1RAcP, interleukin-1 receptor accessory protein; TRAIL, tumor necrosis factor related apoptosis inducing ligand; TNFR1/2, tumor necrosis factor receptor 1 or 2; WT, wildtype.From the