Interleukin-10 induces senescence of activated hepatic stellate cells via STAT3-p53 pathway to attenuate liver fibrosis
| Autor: | Xiao-Zhong Wang, Ming-Hua Chen, Zhixin Chen, Qi-Lan Guo, Qing-Duo Chen, Yue-Hong Huang |
|---|---|
| Rok vydání: | 2019 |
| Předmět: |
0301 basic medicine
Senescence Liver Cirrhosis Male STAT3 Transcription Factor Cell cycle checkpoint Rats Sprague-Dawley 03 medical and health sciences 0302 clinical medicine Hepatic Stellate Cells Animals STAT3 Cellular Senescence biology Cell growth Chemistry Cell Biology Transfection beta-Galactosidase Cell biology Interleukin-10 Rats Interleukin 10 030104 developmental biology 030220 oncology & carcinogenesis biology.protein Hepatic stellate cell Tumor Suppressor Protein p53 Hepatic fibrosis |
| Zdroj: | Cellular signalling. 66 |
| ISSN: | 1873-3913 |
| Popis: | Hepatic fibrosis is a wound healing process which results in deposition of excessive abnormal extracellular matrix (ECM) in response to various liver injuries. Activated hepatic stellate cells (HSCs) are the major sources of ECM and induction of senescence of activated HSCs is an attractive therapeutic strategy for liver fibrosis. Our previous studies have shown that interleukin-10 (IL-10) attenuates the carbon tetrachloride (CCL4) - and porcine serum-induced liver fibrosis in rats. However, little is known about the mechanisms of IL-10 regulating the senescence of activated HSCs. The aim of this study is to uncover the underlying pathway by which IL-10 mediates activated HSCs senescence to attenuate liver fibrosis. In vivo, we found that IL-10 gene by hydrodynamics-based transfection attenuated CCL4-induced liver fibrosis associated with senescence of activated HSCs in rats. In vitro experiment confirmed that IL-10 could induce senescence of activated HSCs via inhibiting cell proliferation, inducing cell cycle arrest, increasing the SA-β-Gal activity and enhancing expression of senescence marker protein p53 and p21. Treatment with Pifithrin-α, a specific inhibitor of p53, could abrogate IL-10-increased SA-β-Gal activity and expression of P53 and P21in activated HSCs. Lastly, IL-10 also increased the expression of total and phosphorylated signal transducers and activators of transcription 3(STAT3) and promoted phosphorylated STAT3 translocation from cytoplasm to nucleus. Treatment with cryptotanshinone, a specific inhibitor of STAT3, could inhibit the phosphorylation of STAT3 and its downstream proteins p53 and p21 expression and decrease the activity of SA-β-Gal in activated HSCs induced by IL-10. Taken together, IL-10 induced senescence of activated HSCs via STAT3-p53 pathway to attenuate liver fibrosis in rats and present study will provide a new mechanism of antifibrotic effects of IL-10. |
| Databáze: | OpenAIRE |
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