120 IFN-G INHIBITS HEPATIC PROGENITOR CELL ACTIVATION IN CHRONIC LIVER DAMAGE

Abstract

Hepatic fibrosis represents a significant health problem worldwide of which no acceptable therapy exists. It is associated with the accumulation of extracellular matrix in response to acute or chronic liver injury and may ultimately lead to cirrhosis. Combined with our recent findings that showed upregulation of Interleukin (IL)-33 in different models of experimental fibrosis, we were endorsed to further investigate the role of IL-33 in liver fibrosis. IL-33, a novel member of IL-1 family of cytokines signalling via IL-1 receptor-related protein ST2, is known to be involved in several autoimmune and inflammatory disorders; however, its function in liver fibrosis still remains ambiguous. To address this question, we analyzed IL-33 transgenic, expression vector-based overexpressing, knockout and receptor (ST2) knockout mice. Different experimental fibrosis models were assessed, at which point IL-33 knockout mice showed protection ascertained by collagen-specific staining, hydroxyproline assay and realtime PCR. In order to analyze profibrotic cellular targets, bone marrow cells from IL-33 receptor knockout (ST2) and wildtype mice were transplanted into lethally radiated wildtype recipients, followed by IL-33 injection after transfer recovery. ST2 mice revealed protection against fibrosis indicating to the relevance of hematopoietic cells in the setting. Gene chip analysis of liver from IL-33 overexpressing mice identified several gene candidates that are differentially regulated during fibrosis, including type 2 IL-4 receptor (IL-4R) signaling molecules. IL-33 overexpression in IL-4Raand IL-13 knockout mice exhibited predominant protection in fibrosis. Similarly, mast cell deficiency is also likely to protect mice, demonstrating the importance of these cells in fibrosis. Based on these results we conclude that IL-33 signal-associated pathways have a considerable role in the development of liver fibrosis. Therefore, our findings may have important implications for therapeutic interventions across a range of fibrosis-based diseases.