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STAT3-mediated attenuation of CCl4-induced mouse liver fibrosis by the protein kinase inhibitor sorafenib.
J Autoimmun. 2013 Oct; 46:25-34.JA

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+Show Affiliations

Liver Immunology Laboratory, Institute of Immunology and School of Life Sciences, University of Science and Technology of China, Hefei 230027, China. Electronic address: adbxdyr@mail.ustc.edu.cn.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

23948302

Citation

Deng, Yan-Ru, et al. "STAT3-mediated Attenuation of CCl4-induced Mouse Liver Fibrosis By the Protein Kinase Inhibitor Sorafenib." Journal of Autoimmunity, vol. 46, 2013, pp. 25-34.
Deng YR, Ma HD, Tsuneyama K, et al. STAT3-mediated attenuation of CCl4-induced mouse liver fibrosis by the protein kinase inhibitor sorafenib. J Autoimmun. 2013;46:25-34.
Deng, Y. R., Ma, H. D., Tsuneyama, K., Yang, W., Wang, Y. H., Lu, F. T., Liu, C. H., Liu, P., He, X. S., Diehl, A. M., Gershwin, M. E., & Lian, Z. X. (2013). STAT3-mediated attenuation of CCl4-induced mouse liver fibrosis by the protein kinase inhibitor sorafenib. Journal of Autoimmunity, 46, 25-34. https://doi.org/10.1016/j.jaut.2013.07.008
Deng YR, et al. STAT3-mediated Attenuation of CCl4-induced Mouse Liver Fibrosis By the Protein Kinase Inhibitor Sorafenib. J Autoimmun. 2013;46:25-34. PubMed PMID: 23948302.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - STAT3-mediated attenuation of CCl4-induced mouse liver fibrosis by the protein kinase inhibitor sorafenib. AU - Deng,Yan-Ru, AU - Ma,Hong-Di, AU - Tsuneyama,Koichi, AU - Yang,Wei, AU - Wang,Yin-Hu, AU - Lu,Fang-Ting, AU - Liu,Cheng-Hai, AU - Liu,Ping, AU - He,Xiao-Song, AU - Diehl,Anna Mae, AU - Gershwin,M Eric, AU - Lian,Zhe-Xiong, Y1 - 2013/08/13/ PY - 2013/07/12/received PY - 2013/07/18/accepted PY - 2013/8/17/entrez PY - 2013/8/21/pubmed PY - 2014/6/3/medline KW - ALT KW - CCl(4) KW - ECM KW - EMT KW - H&E KW - HCC KW - HGF KW - HSC KW - IL-6 KW - JAK KW - Janus tyrosine kinases KW - Kupffer cell KW - Liver fibrosis KW - MMP KW - NASH KW - PDGF KW - SORA KW - STAT3 KW - Sorafenib KW - TGF-β KW - Timp KW - VEGF KW - carbon tetrachloride KW - epithelial–mesenchymal transition KW - extracellular matrix KW - hematoxylin-eosin KW - hepatic stellate cell KW - hepatocellular carcinoma KW - hepatocyte growth factor KW - interleukin-6 KW - matrix metalloproteinase KW - non-alcoholic steatohepatitis KW - p-c-Raf KW - pErk KW - pMEK KW - pSTAT3 KW - phosphorylated MEK1/2 KW - phosphorylated STAT3 KW - phosphorylated c-Raf KW - phosphorylated p44/42 MAPK(Erk1/2) KW - platelet-derived growth factor KW - serum alanine aminotransferase KW - signal transducer and activator of transcription 3 KW - sorafenib KW - tissue inhibitor of metalloproteinase KW - transforming growth factor-β KW - vascular endothelial growth factor KW - wild type KW - wt KW - α-SMA KW - α-smooth muscle actin SP - 25 EP - 34 JF - Journal of autoimmunity JO - J Autoimmun VL - 46 N2 - 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. SN - 1095-9157 UR - https://www.unboundmedicine.com/medline/citation/23948302/STAT3_mediated_attenuation_of_CCl4_induced_mouse_liver_fibrosis_by_the_protein_kinase_inhibitor_sorafenib_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0896-8411(13)00104-2 DB - PRIME DP - Unbound Medicine ER -