3-Aminobenzamide Prevents Concanavalin A-Induced Acute Hepatitis by an Anti-inflammatory and Anti-oxidative Mechanism

Joram Wardi*, Orna Ernst, Anna Lilja, Hussein Aeed, Sebastián Katz, Idan Ben-Nachum, Iris Ben-Dror, Dolev Katz, Olga Bernadsky, Rajendar Kandhikonda, Yona Avni, Iain D.C. Fraser, Roy Weinstain, Alexander Biro, Tsaffrir Zor

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

Abstract

Background and Aims: Concanavalin A is known to activate T cells and to cause liver injury and hepatitis, mediated in part by secretion of TNFα from macrophages. Poly(ADP-ribose) polymerase-1 (PARP-1) inhibitors have been shown to prevent tissue damage in various animal models of inflammation. The objectives of this study were to evaluate the efficacy and mechanism of the PARP-1 inhibitor 3-aminobenzamide (3-AB) in preventing concanavalin A-induced liver damage. Methods: We tested the in vivo effects of 3-AB on concanavalin A-treated mice, its effects on lipopolysaccharide (LPS)-stimulated macrophages in culture, and its ability to act as a scavenger in in vitro assays. Results: 3-AB markedly reduced inflammation, oxidative stress, and liver tissue damage in concanavalin A-treated mice. In LPS-stimulated RAW264.7 macrophages, 3-AB inhibited NFκB transcriptional activity and subsequent expression of TNFα and iNOS and blocked NO production. In vitro, 3-AB acted as a hydrogen peroxide scavenger. The ROS scavenger N-acetylcysteine (NAC) and the ROS formation inhibitor diphenyleneiodonium (DPI) also inhibited TNFα expression in stimulated macrophages, but unlike 3-AB, NAC and DPI were unable to abolish NFκB activity. PARP-1 knockout failed to affect NFκB and TNFα suppression by 3-AB in stimulated macrophages. Conclusions: Our results suggest that 3-AB has a therapeutic effect on concanavalin A-induced liver injury by inhibiting expression of the key pro-inflammatory cytokine TNFα, via PARP-1-independent NFκB suppression and via an NFκB-independent anti-oxidative mechanism.

Original languageEnglish
Pages (from-to)3382-3397
Number of pages16
JournalDigestive Diseases and Sciences
Volume63
Issue number12
DOIs
StatePublished - 1 Dec 2018

Keywords

  • Inflammation
  • Liver failure
  • Macrophages
  • NFκB
  • Reactive oxygen species
  • TNFα

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