Inhibition of spleen tyrosine kinase activation ameliorates inflammation, cell death, and steatosis in alcoholic liver disease
Authors
Bukong, Terence N.Iracheta-Vellve, Arvin
Saha, Banishree
Ambade, Aditya
Satishchandran, Abhishek
Gyongyosi, Benedek
Lowe, Patrick
Catalano, Donna
Kodys, Karen
Szabo, Gyongyi
UMass Chan Affiliations
UMass Metabolic NetworkGraduate School of Biomedical Sciences, Translational Science Program
Graduate School of Biomedical Sciences, MD/PhD Program
Department of Medicine, Division of Gastroenterology
Document Type
Journal ArticlePublication Date
2016-10-01
Metadata
Show full item recordAbstract
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.Source
Hepatology. 2016 Oct;64(4):1057-71. doi: 10.1002/hep.28680. Epub 2016 Jul 22. Link to article on publisher's siteDOI
10.1002/hep.28680Permanent Link to this Item
http://hdl.handle.net/20.500.14038/28809PubMed ID
27302565Notes
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 PubMedae974a485f413a2113503eed53cd6c53
10.1002/hep.28680