Interleukin-33 Drives Hepatic Fibrosis Through Activation Of Hepatic Stellate Cells

Liver fibrosis is one of the major diseases that endanger the health of Chinese people.Liver fibrosis,featuring its long clinical course,intractable and relatively bad prognosis,severly threatened the life quality of patients and challenged public health resources distribution.It is well accepted that the non-resolvable hepatitis caused by viral infection is one of the most important epitology for liver fibrosis development.Persistent liver cells death,infiltration of inmmunal cells,compensatory hyperplasia and formation of pseudo-lobule in the liver is generally considered to be the pathological process of inflammation-promoted liver fibrosis.Thus,to understand the signaling pathways driving these immune processes during liver fibrosis is important for developing novel treatments for this dreadful disease.Interleukin-33(IL-33),an IL-1-related cytokine,emerged as an important cytokine for Th2 driven cytokine which is released upon cell death and increased IL-33 can be detected in severe inflammation in vivo.IL-33 binding to the ST2 receptor produces pro-inflammatory cytokines and Th2 cytokines production.By far,the role of IL-33 in liver fibrosis did not fully investigated.Thus,we investigated the role of IL-33/ST2 signaling by using experimental model of hepatic fibrosis and the clinic specimen aquired from our center.The main results from my PhD are presented as followings:We report increased hepatic IL-33 expression in the murine BDL model of fibrosis and in surgical samples obtained from patients with liver fibrosis.Liver inflammation,pro-inflammatory cells infiltration and fibrosis are reduced in the absence of IL-33/ST2 receptor and the activation of hepatic stellate cells(HSCs)is decreased in ST2 deficient mice.Recombinant IL-33 activated HSCs isolated from C57BL/6 mice with the expression of IL-6,TGF-?,a-SMA and collagen,which is abrogated in the absence of ST2 or by pharmacological inhibition of MAPK signaling.Finally,administration of recombinant IL-33 significantly increased hepatic inflammation in sham operated BL6 mice,but did not enhance BDL induced hepatic inflammation and fibrosis.In conclusion,BDL induced liver inflammation and fibrosis are dependent on ST2 signaling in HSC and therefore the IL-33/ST2 pathway may be a potential therapeutic target in human patients with chronic hepatitis and liver fibrosis.