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.

• Authors: Yan-Ru Deng, Hong-Di Ma, Koichi Tsuneyama, Wei Yang, Yin-Hu Wang, Fang-Ting Lu, Cheng-Hai Liu, Ping Liu, Xiao-Song He, Anna Mae Diehl, M Eric Gershwin, Zhe-Xiong Lian
• Journal: Journal of autoimmunity (J Autoimmun) Vol. 46 Pg. 25-34 (Oct 2013) ISSN: 1095-9157 [Electronic] England
• PMID: 23948302 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2013 Elsevier Ltd. All rights reserved.

Chemical References

• Acta2 protein, mouse
• Actins
• Collagen Type I
• Collagen Type I, alpha 1 Chain
• Interleukin-6
• Phenylurea Compounds
• Protein Kinase Inhibitors
• STAT3 Transcription Factor
• Stat3 protein, mouse
• Timp1 protein, mouse
• Tissue Inhibitor of Metalloproteinase-1
• Niacinamide
• Sorafenib
• Carbon Tetrachloride

Topics

• Actins (genetics, metabolism)
• Active Transport, Cell Nucleus (drug effects)
• Animals
• Carbon Tetrachloride
• Cell Nucleus (drug effects, metabolism)
• Cells, Cultured
• Collagen Type I (genetics, metabolism)
• Collagen Type I, alpha 1 Chain
• Gene Expression (drug effects)
• Hepatocytes (drug effects, metabolism, pathology)
• Immunoblotting
• Immunohistochemistry
• Interleukin-6 (genetics, metabolism)
• Kinetics
• Kupffer Cells (drug effects, metabolism, pathology)
• Liver (drug effects, metabolism, pathology)
• Liver Cirrhosis (chemically induced, genetics, prevention & control)
• Mice
• Mice, Inbred C57BL
• Mice, Knockout
• Niacinamide (analogs & derivatives, pharmacology)
• Phenylurea Compounds (pharmacology)
• Phosphorylation (drug effects)
• Protein Kinase Inhibitors (pharmacology)
• Reverse Transcriptase Polymerase Chain Reaction
• STAT3 Transcription Factor (genetics, metabolism)
• Sorafenib
• Tissue Inhibitor of Metalloproteinase-1 (genetics, metabolism)