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Inhibition of spleen tyrosine kinase activation ameliorates inflammation, cell death, and steatosis in alcoholic liver disease
University of Massachusetts Medical School Faculty Publications
  • Terence N. Bukong, University of Massachusetts Medical School
  • Arvin Iracheta-Vellve, University of Massachusetts Medical School
  • Banishree Saha, University of Massachusetts Medical School
  • Aditya Ambade, University of Massachusetts Medical School
  • Abhishek Satishchandran, University of Massachusetts Medical School
  • Benedek Gyongyosi, University of Massachusetts Medical School
  • Patrick Lowe, University of Massachusetts Medical School
  • Donna Catalano, University of Massachusetts Medical School
  • Karen Kodys, University of Massachusetts Medical School
  • Gyongyi Szabo, University of Massachusetts Medical School
UMMS Affiliation
Department of Medicine, Division of Gastroenterology; Graduate School of Biomedical Sciences, MD/PhD Program; Graduate School of Biomedical Sciences, Translational Science Program; UMass Metabolic Network
Publication Date
10-1-2016
Document Type
Article
Abstract

The spectrum of alcoholic liver disease (ALD) is a major cause of mortality with limited therapies available. Because alcohol targets numerous signaling pathways in hepatocytes and in immune cells, the identification of a master regulatory target that modulates multiple signaling processes is attractive. In this report, we assessed the role of spleen tyrosine kinase (SYK), a nonreceptor tyrosine kinase, which has a central modulatory role in multiple proinflammatory signaling pathways involved in the pathomechanism of ALD. Using mouse disease models that represent various phases in the progression of human ALD, we found that alcohol, in all of these models, induced SYK activation in the liver, both in hepatocytes and liver mononuclear cells. Furthermore, significant SYK activation also occurred in liver samples and peripheral blood mononuclear cells of patients with ALD/alcoholic hepatitis compared to controls. Functional inhibition of SYK activation in vivo abrogated alcohol-induced hepatic neutrophil infiltration, resident immune cell activation, as well as inflammasome and extracellular signal-regulated kinase 1 and 2-mediated nuclear factor kappa B activation in mice. Strikingly, inhibition of SYK activation diminished alcohol-induced hepatic steatosis and interferon regulatory factor 3-mediated apoptosis.

CONCLUSION: Our data demonstrate a novel, functional, and multicellular role for SYK phosphorylation in modulating immune cell-driven liver inflammation, hepatocyte cell death, and steatosis at different stages of ALD. These novel findings highlight SYK as a potential multifunctional target in the treatment of alcoholic steatohepatitis.

DOI of Published Version
10.1002/hep.28680
Source
Hepatology. 2016 Oct;64(4):1057-71. doi: 10.1002/hep.28680. Epub 2016 Jul 22. Link to article on publisher's site
Comments

Co-authors Satischandran and Lowe are students in the MD/PhD Program at UMass Medical School. Co-author Iracheta-Vellve is a doctoral student in the Translational Science Program in the Graduate School of Biomedical Sciences (GSBS) at UMass Medical School.

Related Resources
Link to Article in PubMed
PubMed ID
27302565
Citation Information
Terence N. Bukong, Arvin Iracheta-Vellve, Banishree Saha, Aditya Ambade, et al.. "Inhibition of spleen tyrosine kinase activation ameliorates inflammation, cell death, and steatosis in alcoholic liver disease" Vol. 64 Iss. 4 (2016) ISSN: 0270-9139 (Linking)
Available at: http://works.bepress.com/gyongyi_szabo/202/