NF-kappaB-activated tissue transglutaminase is involved in ethanol-induced hepatic injury and the possible role of propolis in preventing fibrogenesis

Toxicology. 2008 Apr 18;246(2-3):148-57. doi: 10.1016/j.tox.2008.01.009. Epub 2008 Jan 19.

Abstract

The increased expression and cross-linking activity of tissue transglutaminase (tTG) have been demonstrated in acute liver injury and fibrosis. We focused on the molecular mechanisms that contribute to ethanol-induced tTG expression and investigated the efficacy of propolis components in preventing both the tTG expression in vitro and fibrogenesis in vivo. We demonstrate herein that both ERK1/2 and PI3K/Akt pathways can regulate the effects of ethanol on NF-kappaB-dependent transcription and these signaling pathways may be involved in activation of ethanol-mediated tTG expression. We also found that administration of pinocembrin (PIN), one of the major components of propolis, inhibited tTG activation and significantly prevented the development of thioacetamide (TAA)-induced liver cirrhosis. The present study suggests that tTG may be an important member of the cascade of factors necessary for ethanol-induced liver fibrogenesis and PIN could serve as an anti-fibrogenic agent.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Anti-Infective Agents / chemistry
  • Cell Line, Tumor
  • Disease Models, Animal
  • Dose-Response Relationship, Drug
  • Enzyme Inhibitors / chemistry
  • Enzyme Inhibitors / therapeutic use*
  • Ethanol / toxicity*
  • Flavanones / chemistry
  • Flavanones / therapeutic use*
  • GTP-Binding Proteins
  • Gene Expression Regulation, Enzymologic
  • Hepatocytes / drug effects
  • Hepatocytes / metabolism
  • Humans
  • Liver Cirrhosis, Experimental / enzymology
  • Liver Cirrhosis, Experimental / pathology
  • Liver Cirrhosis, Experimental / prevention & control*
  • Mitogen-Activated Protein Kinase 1 / metabolism
  • Mitogen-Activated Protein Kinase 3 / metabolism
  • NF-kappa B / biosynthesis*
  • Propolis / chemistry
  • Protein Glutamine gamma Glutamyltransferase 2
  • RNA, Messenger / metabolism
  • Rats
  • Transglutaminases / genetics
  • Transglutaminases / metabolism*

Substances

  • Anti-Infective Agents
  • Enzyme Inhibitors
  • Flavanones
  • NF-kappa B
  • RNA, Messenger
  • Ethanol
  • pinocembrin
  • Propolis
  • Protein Glutamine gamma Glutamyltransferase 2
  • Transglutaminases
  • Mitogen-Activated Protein Kinase 1
  • Mitogen-Activated Protein Kinase 3
  • GTP-Binding Proteins