Therapeutic Benefits of Spleen Tyrosine Kinase Inhibitor Administration on Binge Drinking-Induced Alcoholic Liver Injury, Steatosis, and Inflammation in Mice

Terence N. Bukong, Arvin Iracheta-Vellve, Benedek Gyongyosi, Aditya Ambade, Donna Catalano, Karen Kodys, G. Szabó

Research output: Contribution to journalArticle

9 Citations (Scopus)

Abstract

Background: Binge drinking is increasingly recognized as an important cause of liver disease with limited therapeutic options for patients. Binge alcohol use, similar to chronic alcohol consumption, induces numerous deregulated signaling events that drive liver damage, steatosis, and inflammation. In this article, we evaluated the role of spleen tyrosine kinase (SYK), which modulates numerous signaling events previously identified linked in the development alcohol-induced liver pathology. Methods: A 3-day alcohol binge was administered to C57BL/6 female mice, and features of alcoholic liver disease were assessed. Some mice were treated daily with intraperitoneal injections of a SYK inhibitor (R406; 5 to 10 mg/kg body weight) or drug vehicle control. Liver and serum samples were collected and were assessed by Western blotting, biochemical, ELISA, electrophoretic mobility shift assays, real-time quantitative polymerase chain reaction, and histopathological analysis. Results: We found that binge drinking induced significant SYK activation (SYKY525/526) with no change in total SYK expression in the liver. Functional inhibition of SYK activation using a potent SYK inhibitor, R406, was associated with a significant decrease in alcohol-induced hepatic inflammation as demonstrated by decreased phospho-nuclear factor kappa beta (NF-κB) p65, NF-κB nuclear binding, tumor necrosis factor-alpha, and monocyte chemoattractant protein-1 mRNA in the liver. Compared to vehicle controls, SYK inhibitor treatment decreased alcohol binge-induced hepatocyte injury indicated by histology and serum alanine aminotransferase. Strikingly, SYK inhibitor treatment also resulted in a significant reduction in alcohol-induced liver steatosis. Conclusions: Our novel observations demonstrate the role of SYK, activation in the pathomechanism of binge drinking-induced liver disease highlighting SYK a potential multifaceted therapeutic target.

Original languageEnglish
Pages (from-to)1524-1530
Number of pages7
JournalAlcoholism: Clinical and Experimental Research
Volume40
Issue number7
DOIs
Publication statusPublished - Jul 1 2016

Fingerprint

Binge Drinking
Fatty Liver
Liver
Protein-Tyrosine Kinases
Inflammation
Wounds and Injuries
Alcohols
Therapeutics
Chemical activation
Liver Diseases
Syk Kinase
Electrophoretic mobility
Alcoholic Liver Diseases
Histology
Chemokine CCL2
Drug and Narcotic Control
Polymerase chain reaction
Electrophoretic Mobility Shift Assay
Pathology
Intraperitoneal Injections

Keywords

  • Alcoholic Hepatitis
  • Binge Drinking
  • Nonreceptor Tyrosine Kinase

ASJC Scopus subject areas

  • Medicine (miscellaneous)
  • Toxicology
  • Psychiatry and Mental health

Cite this

Therapeutic Benefits of Spleen Tyrosine Kinase Inhibitor Administration on Binge Drinking-Induced Alcoholic Liver Injury, Steatosis, and Inflammation in Mice. / Bukong, Terence N.; Iracheta-Vellve, Arvin; Gyongyosi, Benedek; Ambade, Aditya; Catalano, Donna; Kodys, Karen; Szabó, G.

In: Alcoholism: Clinical and Experimental Research, Vol. 40, No. 7, 01.07.2016, p. 1524-1530.

Research output: Contribution to journalArticle

Bukong, Terence N. ; Iracheta-Vellve, Arvin ; Gyongyosi, Benedek ; Ambade, Aditya ; Catalano, Donna ; Kodys, Karen ; Szabó, G. / Therapeutic Benefits of Spleen Tyrosine Kinase Inhibitor Administration on Binge Drinking-Induced Alcoholic Liver Injury, Steatosis, and Inflammation in Mice. In: Alcoholism: Clinical and Experimental Research. 2016 ; Vol. 40, No. 7. pp. 1524-1530.
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AU - Bukong, Terence N.

AU - Iracheta-Vellve, Arvin

AU - Gyongyosi, Benedek

AU - Ambade, Aditya

AU - Catalano, Donna

AU - Kodys, Karen

AU - Szabó, G.

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N2 - Background: Binge drinking is increasingly recognized as an important cause of liver disease with limited therapeutic options for patients. Binge alcohol use, similar to chronic alcohol consumption, induces numerous deregulated signaling events that drive liver damage, steatosis, and inflammation. In this article, we evaluated the role of spleen tyrosine kinase (SYK), which modulates numerous signaling events previously identified linked in the development alcohol-induced liver pathology. Methods: A 3-day alcohol binge was administered to C57BL/6 female mice, and features of alcoholic liver disease were assessed. Some mice were treated daily with intraperitoneal injections of a SYK inhibitor (R406; 5 to 10 mg/kg body weight) or drug vehicle control. Liver and serum samples were collected and were assessed by Western blotting, biochemical, ELISA, electrophoretic mobility shift assays, real-time quantitative polymerase chain reaction, and histopathological analysis. Results: We found that binge drinking induced significant SYK activation (SYKY525/526) with no change in total SYK expression in the liver. Functional inhibition of SYK activation using a potent SYK inhibitor, R406, was associated with a significant decrease in alcohol-induced hepatic inflammation as demonstrated by decreased phospho-nuclear factor kappa beta (NF-κB) p65, NF-κB nuclear binding, tumor necrosis factor-alpha, and monocyte chemoattractant protein-1 mRNA in the liver. Compared to vehicle controls, SYK inhibitor treatment decreased alcohol binge-induced hepatocyte injury indicated by histology and serum alanine aminotransferase. Strikingly, SYK inhibitor treatment also resulted in a significant reduction in alcohol-induced liver steatosis. Conclusions: Our novel observations demonstrate the role of SYK, activation in the pathomechanism of binge drinking-induced liver disease highlighting SYK a potential multifaceted therapeutic target.

AB - Background: Binge drinking is increasingly recognized as an important cause of liver disease with limited therapeutic options for patients. Binge alcohol use, similar to chronic alcohol consumption, induces numerous deregulated signaling events that drive liver damage, steatosis, and inflammation. In this article, we evaluated the role of spleen tyrosine kinase (SYK), which modulates numerous signaling events previously identified linked in the development alcohol-induced liver pathology. Methods: A 3-day alcohol binge was administered to C57BL/6 female mice, and features of alcoholic liver disease were assessed. Some mice were treated daily with intraperitoneal injections of a SYK inhibitor (R406; 5 to 10 mg/kg body weight) or drug vehicle control. Liver and serum samples were collected and were assessed by Western blotting, biochemical, ELISA, electrophoretic mobility shift assays, real-time quantitative polymerase chain reaction, and histopathological analysis. Results: We found that binge drinking induced significant SYK activation (SYKY525/526) with no change in total SYK expression in the liver. Functional inhibition of SYK activation using a potent SYK inhibitor, R406, was associated with a significant decrease in alcohol-induced hepatic inflammation as demonstrated by decreased phospho-nuclear factor kappa beta (NF-κB) p65, NF-κB nuclear binding, tumor necrosis factor-alpha, and monocyte chemoattractant protein-1 mRNA in the liver. Compared to vehicle controls, SYK inhibitor treatment decreased alcohol binge-induced hepatocyte injury indicated by histology and serum alanine aminotransferase. Strikingly, SYK inhibitor treatment also resulted in a significant reduction in alcohol-induced liver steatosis. Conclusions: Our novel observations demonstrate the role of SYK, activation in the pathomechanism of binge drinking-induced liver disease highlighting SYK a potential multifaceted therapeutic target.

KW - Alcoholic Hepatitis

KW - Binge Drinking

KW - Nonreceptor Tyrosine Kinase

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