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

Publication ,  Journal Article
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, AM; Gershwin, ME; Lian, Z-X
Published in: J Autoimmun
October 2013

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.

Duke Scholars

Published In

J Autoimmun

DOI

EISSN

1095-9157

Publication Date

October 2013

Volume

46

Start / End Page

25 / 34

Location

England

Related Subject Headings

  • Tissue Inhibitor of Metalloproteinase-1
  • Sorafenib
  • STAT3 Transcription Factor
  • Reverse Transcriptase Polymerase Chain Reaction
  • Protein Kinase Inhibitors
  • Phosphorylation
  • Phenylurea Compounds
  • Niacinamide
  • Mice, Knockout
  • Mice, Inbred C57BL
 

Citation

APA
Chicago
ICMJE
MLA
NLM
Deng, Y.-R., Ma, H.-D., Tsuneyama, K., Yang, W., Wang, Y.-H., Lu, F.-T., … Lian, Z.-X. (2013). STAT3-mediated attenuation of CCl4-induced mouse liver fibrosis by the protein kinase inhibitor sorafenib. J Autoimmun, 46, 25–34. https://doi.org/10.1016/j.jaut.2013.07.008
Deng, Yan-Ru, Hong-Di Ma, Koichi Tsuneyama, Wei Yang, Yin-Hu Wang, Fang-Ting Lu, Cheng-Hai Liu, et al. “STAT3-mediated attenuation of CCl4-induced mouse liver fibrosis by the protein kinase inhibitor sorafenib.J Autoimmun 46 (October 2013): 25–34. https://doi.org/10.1016/j.jaut.2013.07.008.
Deng Y-R, Ma H-D, Tsuneyama K, Yang W, Wang Y-H, Lu F-T, et al. STAT3-mediated attenuation of CCl4-induced mouse liver fibrosis by the protein kinase inhibitor sorafenib. J Autoimmun. 2013 Oct;46:25–34.
Deng, Yan-Ru, et al. “STAT3-mediated attenuation of CCl4-induced mouse liver fibrosis by the protein kinase inhibitor sorafenib.J Autoimmun, vol. 46, Oct. 2013, pp. 25–34. Pubmed, doi:10.1016/j.jaut.2013.07.008.
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 AM, Gershwin ME, Lian Z-X. STAT3-mediated attenuation of CCl4-induced mouse liver fibrosis by the protein kinase inhibitor sorafenib. J Autoimmun. 2013 Oct;46:25–34.
Journal cover image

Published In

J Autoimmun

DOI

EISSN

1095-9157

Publication Date

October 2013

Volume

46

Start / End Page

25 / 34

Location

England

Related Subject Headings

  • Tissue Inhibitor of Metalloproteinase-1
  • Sorafenib
  • STAT3 Transcription Factor
  • Reverse Transcriptase Polymerase Chain Reaction
  • Protein Kinase Inhibitors
  • Phosphorylation
  • Phenylurea Compounds
  • Niacinamide
  • Mice, Knockout
  • Mice, Inbred C57BL