Tyrosine kinase SYK is a potential therapeutic target for liver fibrosis
| Autor: | Jacinta A. Holmes, Yuchuan Jiang, Wenyu Lin, Dandan Zheng, Mengxian Tu, Yadi Liao, Weiming Li, Hui Yuan, Bryan C. Fuchs, Xijun Chen, Jian Hong, Lu He, Qimeng Jin, Yingjun Liu, Sai Li, Qiaoting Hu, Zelong Lin, Raymond T. Chung, Lan Wei, Jianning Chen, Anna Lidofsky, Chen Qu |
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| Rok vydání: | 2017 |
| Předmět: |
0301 basic medicine
Male Cirrhosis Indazoles medicine.medical_treatment Drug Evaluation Preclinical Syk chemical and pharmacologic phenomena Liver Cirrhosis Experimental 03 medical and health sciences 0302 clinical medicine Fibrosis medicine Hepatic Stellate Cells Animals Humans Syk Kinase Cellular localization Hepatology business.industry hemic and immune systems Hep G2 Cells medicine.disease digestive system diseases Rats Mice Inbred C57BL 030104 developmental biology Cytokine 030220 oncology & carcinogenesis Pyrazines Cancer research Hepatic stellate cell Hepatocytes Steatohepatitis business Tyrosine kinase |
| Zdroj: | Hepatology (Baltimore, Md.). 68(3) |
| ISSN: | 1527-3350 |
| Popis: | Spleen tyrosine kinase (SYK) plays a critical role in immune cell signaling pathways and has been reported as a biomarker for human hepatocellular carcinoma (HCC). We sought to investigate the mechanism by which SYK promotes liver fibrosis and to evaluate SYK as a therapeutic target for liver fibrosis. We evaluated the cellular localization of SYK and the association between SYK expression and liver fibrogenesis in normal, hepatitis B virus (HBV)-infected, hepatitis C virus (HCV)-infected and non-alcoholic steatohepatitis (NASH) liver tissue (n=36, 127, 22 and 30, respectively). A polymerase chain reaction (PCR) array was used to detect the changes in transcription factor (TF) expression in hepatic stellate cells (HSCs) with SYK knockdown. The effects of SYK antagonism on liver fibrogenesis were studied in LX-2 cells, TWNT-4 cells, primary human HSCs, and three progressive fibrosis/cirrhosis animal models, including a CCL4 mouse model, and diethylnitrosamine (DEN) and bile duct ligation (BDL) rat models. We found that SYK protein in HSCs and hepatocytes correlated positively with liver fibrosis stage in human liver tissue. HBV or HCV infection significantly increased SYK and cytokine expression in hepatocytes. Increasing cytokine production further induced SYK expression and fibrosis-related gene transcription in HSCs. Up-regulated SYK in HSCs promoted HSC activation by increasing the expression of specific TFs related to activation of HSCs. SYK antagonism effectively suppressed liver fibrosis via inhibition of HSC activation, and decreased obstructive jaundice and reduced HCC development in animal models. Conclusion: SYK promotes liver fibrosis via activation of HSCs and is an attractive potential therapeutic target for liver fibrosis and prevention of HCC development. (Hepatology 2018). |
| Databáze: | OpenAIRE |
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