The Study of Interleukin-20 in Liver Disease

Abstract

Interleukin (IL)-20 is a proinflammatory cytokine of the IL-10 family and involved in rheumatoid arthritis atherosclerosis osteoporosis and breast cancer However the pathophysiological roles of IL-20 in liver disease have not been extensively studied We explored the involvement of IL-20 in liver disease and the therapeutic potential of IL-20 antagonists for treating liver fibrosis and hepatocellular carcinoma (HCC) In first part compared with the normal liver tissue from healthy individuals the amount of IL-20 was much higher in hepatocytes and hepatic stellate cells in liver biopsies from patients with fibrosis cirrhosis and hepatocellular carcinoma Carbon tetrachloride (CCl4) treatment induced IL-20 that further upregulated the expression of transforming growth factor (TGF)-β1 and p21WAF1 and resulted in cell cycle arrest in the Clone-9 rat hepatocyte cell line IL-20 activated quiescent rat hepatic stellate cells (HSCs) and upregulated TGF-β1 expression IL-20 also increased TGF-β1 tumor necrosis factor (TNF)-? and type I collagen expression and promoted the proliferation and migration of activated HSCs Serum IL-20 was significantly elevated in mice with short-term and long-term CCl4-induced liver injury In mice with short-term liver injury anti-IL-20 monoclonal antibody (7E) and anti-IL-20 receptor (IL-20R1) monoclonal antibody (51D) attenuated hepatocyte damage caused by CCl4 TGF-β1 and chemokine production In mice with long-term liver injury 7E and 51D inhibited CCl4-induced cell damage TGF-β1 production liver fibrosis HSC activation and extracellular matrix accumulation which was caused by the reduced expression of tissue inhibitors of metalloproteinases as well as increased metalloproteinase (MMP) expression and Col-I production IL-20R1-deficient mice were protected from short-term and long-term liver injury We identified a pivotal role of IL-20 in liver injury and showed that 7E and 51D may be therapeutics for liver fibrosis When the injury is prolonged an inflammatory response is induced which leads either to tissue regeneration and repair in fibrosis cirrhosis and finally hepatocellular carcinoma Furthermore in the second part we explored the function of IL-20 in HCC HCC tumor tissue expressed higher levels of IL-20 than did non-tumor tissue High IL-20 expression in HCC was correlated with poor overall survival (relative risk: > 3) IL-20 and cyclin D1 expression were also highly correlated in HCC patient specimens and 3 human HCC cell lines IL-20 also increased cell proliferation and migration and it regulated MMP-13 TNF-? cyclin D1 and p21WAF1 expression in the murine HCC cell line ML-1 7E attenuated tumor growth in mice inoculated with ML-1 cells The expression of cyclin D1 TNF-? MMP-9 and vascular endothelial growth factor was significantly inhibited after 7E treatment We demonstrate that IL-20 is important in the pathogenesis of HCC and that 7E inhibits HCC tumor progression

Date of Award	2014 Aug 6
Original language	English
Supervisor	Ming-Shi Chang (Supervisor)