Friedelane-type triterpenoids as selective anti-inflammatory agents by regulation of differential signaling pathways in LPS-stimulated macrophages

Toxicol Appl Pharmacol. 2016 Dec 15;313:57-67. doi: 10.1016/j.taap.2016.10.004. Epub 2016 Oct 15.

Abstract

A series of 31 pentacyclic triterpenoids isolated from the root barks of Celastrus vulcanicola and Maytenus jelskii were tested for cytotoxicity and inhibitory activity against lipopolysaccharide (LPS)-induced nitric oxide (NO) production in RAW 264.7 macrophages. Compounds 18 (C18) and 25 (C25) exhibited significant inhibition of LPS-induced NO release at 50 and 25μM concentrations, respectively, and decreased mRNAs of pro-inflammatory cytokines. At the molecular level, C18 neither inhibited LPS-mediated phosphorylation of mitogen activated protein kinases (MAPKs) nor nuclear translocation of nuclear factor kappa beta (NFκB). Instead, C18 enhanced and prolonged nuclear translocation of nuclear factor-erythroid 2-related factor 2 (Nrf2) and increased the expression of its target genes including hemeoxigenase 1 (HO1). C25 efficiently inhibited LPS-mediated phosphorylation of JNK, p38 and ERK, without affecting NFκB or Nrf2 signaling pathways. Both compounds reduced LPS-mediated processing of caspase-1 and the cleavage of interleukin 1β (IL1β) proform, reflecting their ability to target the inflammasome. C25 also counteracted LPS effects on iNOS expression and pro-inflammatory cytokines mRNA levels in Bv-2 microglial cells. The anti-inflammatory effect of both compounds was also assessed in human macrophages. Our results suggest that triterpenoids C18 and C25 possess anti-inflammatory effects, which may be therapeutically relevant for diseases linked to inflammation.

Keywords: Antioxidant enzymes; Inflammation; Lipopolysaccharide; Macrophages; Nitric oxide synthase; Triterpenoids.

MeSH terms

  • Animals
  • Anti-Inflammatory Agents / pharmacology*
  • Caspase 1 / metabolism
  • Cell Line
  • Enzyme Induction
  • Interleukin-1beta / metabolism
  • Lipopolysaccharides / toxicity*
  • Macrophages / drug effects*
  • Macrophages / metabolism
  • Mice
  • Mitogen-Activated Protein Kinases / metabolism
  • Nitric Oxide Synthase Type II / biosynthesis
  • Nitric Oxide Synthase Type II / genetics
  • Nitric Oxide Synthase Type II / metabolism
  • Phosphorylation
  • RNA, Messenger / genetics
  • Signal Transduction / drug effects*
  • Triterpenes / pharmacology*

Substances

  • Anti-Inflammatory Agents
  • Interleukin-1beta
  • Lipopolysaccharides
  • RNA, Messenger
  • Triterpenes
  • friedelane
  • Nitric Oxide Synthase Type II
  • Mitogen-Activated Protein Kinases
  • Caspase 1