Atrovirinone inhibits pro-inflammatory mediator release from murine macrophages and human whole blood

Immunol Cell Biol. 2006 Jun;84(3):250-8. doi: 10.1111/j.1440-1711.2006.01426.x.

Abstract

Many plant-derived natural compounds have been reported previously to inhibit the production of important pro-inflammatory mediators such as nitric oxide, prostaglandin E2, TNF-alpha and reactive oxygen species by suppressing inducible enzyme expression via inhibition of the mitogen-activated protein kinase pathway and nuclear translocation of critical transcription factors. This study evaluates the effects of atrovirinone [2-(1-methoxycarbonyl-4,6-dihydroxyphenoxy)-3-methoxy-5,6-di-(3-methyl-2-butenyl)-1,4-benzoquinone)], a benzoquinone that we have previously isolated from Garcinia atroviridis, on two cellular systems that are repeatedly used in the analysis of anti-inflammatory bioactive compounds, namely, RAW 264.7 macrophage cells and whole blood. Atrovirinone inhibited the production of both nitric oxide and prostaglandin E2 from LPS-induced and IFN-gamma-induced RAW 264.7 cells and whole blood, with inhibitory concentration (IC)50 values of 4.62 +/- 0.65 and 9.33 +/- 1.47 micromol/L, respectively. Analysis of thromboxane B2 (TXB2) secretion from whole blood stimulated by either the cyclooxygenase (COX)-1 or the COX-2 pathway showed that atrovirinone inhibits the generation of TXB2 by both pathways, with IC50 values of 7.41 +/- 0.92 and 2.10 +/- 0.48 micromol/L, respectively. Analysis of IC50 ratios showed that atrovirinone was more COX-2 selective in its inhibition of TXB2, with a ratio of 0.32. Atrovirinone also inhibited the generation of intracellular reactive oxygen species and the secretion of TNF-alpha from RAW 264.7 cells in a dose-responsive manner, with IC50 values of 5.99 +/- 0.62 and 11.56 +/- 0.04 micromol/L, respectively. Lipoxygenase activity was also moderately inhibited by atrovirinone. Our results suggest that atrovirinone acts on important pro-inflammatory mediators possibly by the inhibition of the nuclear factor-kappaB pathway and also by the inhibition of the COX/lipoxygenase enzyme activity.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Benzoquinones / pharmacology*
  • Cell Line
  • Cells, Cultured
  • Cyclooxygenase 1 / metabolism
  • Cyclooxygenase 2 / metabolism
  • Dinoprostone / metabolism*
  • Erythrocytes / drug effects*
  • Humans
  • Interferon-gamma / pharmacology
  • Lipopolysaccharides / pharmacology
  • Lipoxygenase / chemistry
  • Lipoxygenase / metabolism
  • Macrophages / drug effects*
  • Mice
  • NF-kappa B / metabolism
  • Nitric Oxide / metabolism*
  • Nitrites / metabolism
  • Oxidative Stress
  • Signal Transduction
  • Tumor Necrosis Factor-alpha / metabolism

Substances

  • Benzoquinones
  • Lipopolysaccharides
  • NF-kappa B
  • Nitrites
  • Tumor Necrosis Factor-alpha
  • atrovirinone
  • Nitric Oxide
  • Interferon-gamma
  • Lipoxygenase
  • Cyclooxygenase 1
  • Cyclooxygenase 2
  • Dinoprostone