Gambogic acid induces heme oxygenase-1 through Nrf2 signaling pathway and inhibits NF-κB and MAPK activation to reduce inflammation in LPS-activated RAW264.7 cells

Biomed Pharmacother. 2019 Jan:109:555-562. doi: 10.1016/j.biopha.2018.10.112. Epub 2018 Nov 3.

Abstract

Gambogic acid (GA), a natural product with a xanthone structure, was previously demonstrated to exert anti-inflammatory effects. The aim of this study was to evaluate the anti-inflammatory activity of GA on LPS-stimulated mouse macrophage RAW264.7 and its anti-inflammatory mechanism. Pretreatment with GA inhibited LPS-induced production of nitric oxide (NO) and prostaglandin E2 (PGE2) through reducing the expressions of inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2). GA also decreased the expressions of pro-inflammatory cytokines, including TNF-α, IL-6 and IL-1β. The activation of nuclear factor-κB (NF-κB) and the Mitogen activated phosphokinases (MAPKs) regulates pro-inflammatory factors. Further experiments demonstrated that the nuclear translocation of NF-κB, a promoting regulator in inflammation, was blocked via inhibiting the phosphorylation event of IκBα by GA. Meanwhile, the Mitogen activated phosphokinase (MAPK) signaling pathways were also suppressed. However, activation of nuclear factor erythroid 2-related factor (Nrf2) can inhibit inflammation. GA could activate the nucleus translocation of Nrf2 and up-regulated the expression of heme oxygenase-1 (HO-1). Taken together, GA exhibited its anti-inflammatory activities through Nrf2 activation and NF-κB depression, thus could be a candidate for the prevention and treatment of diseases that involve excessive inflammation.

Keywords: Gambogic acid; Inflammation; MAPKs; NF-κB; Nrf2.

MeSH terms

  • Animals
  • Anti-Inflammatory Agents / pharmacology
  • Dose-Response Relationship, Drug
  • Enzyme Activation / drug effects
  • Enzyme Activation / physiology
  • Heme Oxygenase-1 / biosynthesis*
  • Inflammation Mediators / antagonists & inhibitors
  • Inflammation Mediators / metabolism*
  • Lipopolysaccharides / toxicity
  • MAP Kinase Signaling System / drug effects
  • MAP Kinase Signaling System / physiology*
  • Membrane Proteins / biosynthesis*
  • Mice
  • NF-E2-Related Factor 2 / agonists
  • NF-E2-Related Factor 2 / metabolism*
  • NF-kappa B / antagonists & inhibitors
  • NF-kappa B / metabolism*
  • RAW 264.7 Cells
  • Signal Transduction / drug effects
  • Signal Transduction / physiology
  • Xanthones / pharmacology*

Substances

  • Anti-Inflammatory Agents
  • Inflammation Mediators
  • Lipopolysaccharides
  • Membrane Proteins
  • NF-E2-Related Factor 2
  • NF-kappa B
  • Nfe2l2 protein, mouse
  • Xanthones
  • gambogic acid
  • Heme Oxygenase-1
  • Hmox1 protein, mouse