Interleukin (IL)‐20 is a proinflammatory cytokine of the IL‐10 family and involved in rheumatoid arthritis, atherosclerosis, stroke, and osteoporosis. However, the pathophysiological roles of IL‐20 in liver injury have not been extensively studied. We explored the involvement of IL‐20 in liver injury and the therapeutic potential of IL‐20 antagonists for treating liver fibrosis. Compared with 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 up‐regulated 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 up‐regulated TGF‐β1 expression. IL‐20 also increased TGF‐β1, tumor necrosis factor (TNF)‐α, and type I collagen (Col‐I) 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 expression and Col‐I production. IL‐20R1‐deficient mice were protected from short‐term and long‐term liver injury. Conclusion: We identified a pivotal role of IL‐20 in liver injury and showed that 7E and 51D may be therapeutic for liver fibrosis. (Hepatology 2014;60:1003–1014)

Interleukin (IL)-20 is a proinflammatory cytokine involved in rheumatoid arthritis, atherosclerosis, and osteoporosis. However, the role of IL-20 in hepatocellular carcinoma (HCC) is unclear. We explored the function of IL-20 in HCC. Tumor tissue samples were analyzed the expression of IL-20 and cyclin D1 by using immunohistochemistry staining and quantitative real-time polymerase chain reaction (qRT-PCR) analysis. To examine the role of anti-IL-20 monoclonal antibody (7E) in tumor growth, BALB/c mice was injected with ML-1 cells and treated with 7E. 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 matrix metalloproteinase (MMP)-13, tumor necrosis factor (TNF)-α, cyclin D1, and p21WAF1 expression in ML-1 cells. 7E attenuated tumor growth in mice inoculated with ML-1 cells. The expression of cyclin D1, TNF-α, MMP-9, and vascular endothelial growth factor was significantly inhibited after 7E treatment. The findings of this study suggest that IL-20 plays a role in the tumor progression of HCC.