Liver Immunology Laboratory, Institute of Immunology and School of Life Sciences, University of Science and Technology of China, Hefei 230027, China.
J Autoimmun. 2013 Oct;46:25-34. doi: 10.1016/j.jaut.2013.07.008. Epub 2013 Aug 13.
There have been major advances in defining the immunological events associated with fibrosis in various chronic liver diseases. We have taken advantage of this data to focus on the mechanisms of action of a unique multi-kinase inhibitor, coined sorafenib, on CCl4-induced murine liver fibrosis, including the effects of this agent in models of both acute and chronic CCl4-mediated pathology. Importantly, sorafenib significantly attenuated chronic liver injury and fibrosis, including reduction in liver inflammation and histopathology as well as decreased expression of liver fibrosis-related genes, including α-smooth muscle actin, collagen, matrix metalloproteinases and the tissue inhibitor of metalloproteinase-1. Furthermore, sorafenib treatment resulted in translocation of cytoplasmic STAT3 to the nucleus in its active form. Based on this observation, we used hepatocyte-specific STAT3 knockout (STAT3(Hep-/-)) mice to demonstrate that hepatic STAT3 was critical for sorafenib-mediated protection against liver fibrosis, and that the upregulation of STAT3 phosphorylation was dependent on Kupffer cell-derived IL-6. In conclusion, these data reflect the clinical potential of the multi-kinase inhibitor sorafenib for the prevention of fibrosis as well as the treatment of established liver fibrosis and illustrate the immunological mechanisms that underlie the protective effects of sorafenib.
在定义各种慢性肝病纤维化相关的免疫学事件方面已经取得了重大进展。我们利用这些数据来关注一种独特的多激酶抑制剂（索拉非尼）在 CCl4 诱导的小鼠肝纤维化中的作用机制，包括该药物在急性和慢性 CCl4 介导的病理学模型中的作用。重要的是，索拉非尼显著减轻慢性肝损伤和纤维化，包括减少肝炎症和组织病理学变化，以及降低与肝纤维化相关的基因的表达，包括α-平滑肌肌动蛋白、胶原、基质金属蛋白酶和金属蛋白酶组织抑制剂-1。此外，索拉非尼治疗导致细胞质 STAT3 向其活性形式的核内易位。基于这一观察结果，我们使用肝细胞特异性 STAT3 敲除（STAT3(Hep-/-)）小鼠来证明肝 STAT3 对于索拉非尼介导的肝纤维化保护至关重要，并且 STAT3 磷酸化的上调依赖于库普弗细胞衍生的 IL-6。总之，这些数据反映了多激酶抑制剂索拉非尼在预防纤维化以及治疗已建立的肝纤维化方面的临床潜力，并说明了索拉非尼保护作用的免疫学机制。
