P094 NKT cells and TRAIL induce hepatocyte IL-33 in murine acute hepatitis

Introduction Interleukin-33 (IL-33), a cytokine of IL-1 family, is primarily expressed by several cell types and recently IL-33/ST2 axis was found to be crucial in liver pathology [1] , [2] . IL-33 interacts via its specific receptors, ST2 and IL-1RAcP, which are mainly expressed by immune cells. Beside, IL-33 is thought to be released during cellular death and it is hypothesized that IL-33 can act as an alarmin cytokine during acute phase of disease, like HMGB1 is known. Methods We investigated the expression and regulation of IL-33 in hepato-cellular death way in mice in developing several models of acute hepatitis, including concanavalin A (ConA), anti-Fas/Jo2 and D-GalN-TNF- α induced hepatitis. Further, by using TRAIL, CD1d and IL-33 deficient mice in ConA-induced liver injury, we studied the expression and function of IL-33. Results We show that IL-33 was present at low levels constitutively in vascular endothelial and sinusoidal endothelial cells while it was clearly induced in these cells after ConA, Fas/Jo2 and D-GalN-TNF- α administration. Interestingly, the hepatocytes strongly expressed nuclear IL-33 specifically in ConA-induced hepatitis compared to other models. We show that the regulation of IL-33 in hepatocytes was via NKT cells [3] and also TRAIL as injection of recombinant TRAIL in CD1d-/- mice after ConA priming induced IL-33 in hepatocytes. Finally, 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 In conclusion, we demonstrate that the expression of IL-33 during acute hepatitis is dependent on NKT cells and TRAIL.