STAT3-mediated attenuation of CCl4-induced mouse liver fibrosis by the protein kinase inhibitor sorafenib

Abstract

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.

Keywords: ALT; CCl(4); ECM; EMT; H&E; HCC; HGF; HSC; IL-6; JAK; Janus tyrosine kinases; Kupffer cell; Liver fibrosis; MMP; NASH; PDGF; SORA; STAT3; Sorafenib; TGF-β; Timp; VEGF; carbon tetrachloride; epithelial–mesenchymal transition; extracellular matrix; hematoxylin-eosin; hepatic stellate cell; hepatocellular carcinoma; hepatocyte growth factor; interleukin-6; matrix metalloproteinase; non-alcoholic steatohepatitis; p-c-Raf; pErk; pMEK; pSTAT3; phosphorylated MEK1/2; phosphorylated STAT3; phosphorylated c-Raf; phosphorylated p44/42 MAPK(Erk1/2); platelet-derived growth factor; serum alanine aminotransferase; signal transducer and activator of transcription 3; sorafenib; tissue inhibitor of metalloproteinase; transforming growth factor-β; vascular endothelial growth factor; wild type; wt; α-SMA; α-smooth muscle actin.