IL-20 and IL-20R1 antibodies protect against liver fibrosis.
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 p21(WAF1) 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.


CONCLUSIONS
We identified a pivotal role of IL-20 in liver injury and showed that 7E and 51D may be therapeutic for liver fibrosis.
Institute of Clinical Pharmacy and Pharmaceutical Sciences.
Yi-Shu
YS
Chiu
Chi-Chen
CC
Wei
Yih-Jyh
YJ
Lin
Yu-Hsiang
YH
Hsu
Ming-Shi
MS
Chang
D000818:Animals; D000911:Antibodies, Monoclonal / Q000627:therapeutic use*; D002252:Carbon Tetrachloride Poisoning / Q000150:complications / Q000378:metabolism*; D016022:Case-Control Studies; D002460:Cell Line; D056486:Chemical and Drug Induced Liver Injury / Q000150:complications / Q000378:metabolism*; D004195:Disease Models, Animal; D006801:Humans; D007378:Interleukins / Q000037:antagonists & inhibitors / Q000276:immunology* / Q000378:metabolism; D008103:Liver Cirrhosis / Q000209:etiology / Q000276:immunology* / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D051381:Rats; D017207:Rats, Sprague-Dawley; D018123:Receptors, Interleukin / Q000276:immunology* / Q000378:metabolism
D000911:Antibodies, Monoclonal; D007378:Interleukins; D018123:Receptors, Interleukin; C492510:interleukin-20 receptor; C422042:interleukin 20