Pentoxifylline prevents concanavalin A-induced hepatitis by reducing tumor necrosis factor α levels and inhibiting adhesion of T lymphocytes to extracellular matrix

Haim Shirin, Rafael Bruck, Hussein Aeed, Daniela Frenkel, Gabriel Kenet, Liliana Zaidel, Yona Avni, Zamir Halpern, Rami Hershkoviz

Research output: Contribution to journalArticlepeer-review

Abstract

Background/Aims: Concanavalin A activates T lymphocytes and causes T cell-mediated hepatic injury in mice. Tumor necrosis factor a is a critical mediator in this experimental model. T-cell-mediated liver injury involves the migration of immune cells, notably CD4+ T lymphocytes, into liver tissue. Pentoxifylline is a strong suppresser of tumor necrosis factor a release and prevents leukocyte adherence to vascular endothelium and down- regulates the expression of intercellular adhesion molecule-1 in monocytes. In this study, we examined the efficacy of pentoxifylline as a potential therapeutic compound for the treatment of concanavalin A hepatitis. Methods: Balb/c mice were injected with 12 mg/kg concanavalin A with or without a single injection of pentoxifylline (5-300 mg/kg), 2 h prior to concanavalin A administration. Liver damage was evaluated by determining serum levels of liver enzymes and tumor necrosis factor a, and hepatic histopathology compared to mice treated with concanavalin A only. We also assessed the effects of pentoxifylline on the adhesive properties of T lymphocytes to fibronectin, as a paradigm for immune cell-extracellular matrix interactions required for migration. Results: Pretreatment with pentoxifylline significantly reduced serum levels of liver enzymes (3800±650 vs 150±28 IU/I) and tumor necrosis factor α (710±105 vs 113±15 pg/ml) with no evidence of inflammation in histopathologic examination compared to control mice treated with concanavalin A. Pentoxifylline also inhibited the binding of murine T cells to fibronectin. All the effects of pentoxifylline were dose-dependent. Conclusions: These results indicate that high doses of pentoxifylline can prevent concanavalin A hepatitis by suppression of tumor necrosis factor a release and inhibition of T cells adhesion to extracellular matrix.

Original languageEnglish
Pages (from-to)60-67
Number of pages8
JournalJournal of Hepatology
Volume29
Issue number1
DOIs
StatePublished - Jul 1998
Externally publishedYes

Keywords

  • Cytokines
  • Hepatitis
  • Pentoxifylline

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