6-Shogaol suppressed lipopolysaccharide-induced up-expression of iNOS and COX-2 in murine macrophages

Mol Nutr Food Res. 2008 Dec;52(12):1467-77. doi: 10.1002/mnfr.200700515.

Abstract

Ginger, the rhizome of Zingiber officinale, is a traditional medicine with carminative effect, antinausea, anti-inflammatory, and anticarcinogenic properties. In this study, we investigated the inhibitory effects of 6-shogaol and a related compound, 6-gingerol, on the induction of nitric oxide synthase (NOS) and cyclooxygenase-2 (COX-2) in murine RAW 264.7 cells activated with LPS. Western blotting and reverse transcription-PCR analyses demonstrated that 6-shogaol significantly blocked protein and mRNA expression of inducible NOS (iNOS) and COX-2 in LPS-induced macrophages. The in vivo anti-inflammatory activity was evaluated by a topical 12-O-tetradecanoylphorbol 13-acetate (TPA) application to mouse skin. When applied topically onto the shaven backs of mice prior to TPA, 6-shogaol markedly inhibited the expression of iNOS and COX-2 proteins. Treatment with 6-shogaol resulted in the reduction of LPS-induced nuclear translocation of nuclear factor-kappaB (NF kappaB) subunit and the dependent transcriptional activity of NF kappaB by blocking phosphorylation of inhibitor kappaB (I kappaB)alpha and p65 and subsequent degradation of I kappaB alpha. Transient transfection experiments using NF kappaB reporter constructs indicated that 6-shogaol inhibits the transcriptional activity of NF kappaB in LPS-stimulated mouse macrophages. We found that 6-shogaol also inhibited LPS-induced activation of PI3K/Akt and extracellular signal-regulated kinase 1/2, but not p38 mitogen-activated protein kinase (MAPK). Taken together, these results show that 6-shogaol downregulates inflammatory iNOS and COX-2 gene expression in macrophages by inhibiting the activation of NF kappaB by interfering with the activation PI3K/Akt/I kappaB kinases IKK and MAPK.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Catechols / pharmacology*
  • Cells, Cultured
  • Cyclooxygenase 2 / genetics*
  • Dinoprostone / biosynthesis
  • Extracellular Signal-Regulated MAP Kinases / metabolism
  • Fatty Alcohols / pharmacology
  • Female
  • Gene Expression Regulation, Enzymologic / drug effects*
  • I-kappa B Proteins / metabolism
  • Lipopolysaccharides / antagonists & inhibitors*
  • Macrophages / enzymology*
  • Mice
  • Mice, Inbred ICR
  • NF-KappaB Inhibitor alpha
  • NF-kappa B / metabolism
  • Nitric Oxide Synthase Type II / genetics*
  • Phosphatidylinositol 3-Kinases / metabolism
  • Skin / enzymology
  • p38 Mitogen-Activated Protein Kinases / metabolism

Substances

  • Catechols
  • Fatty Alcohols
  • I-kappa B Proteins
  • Lipopolysaccharides
  • NF-kappa B
  • Nfkbia protein, mouse
  • NF-KappaB Inhibitor alpha
  • shogaol
  • gingerol
  • Nitric Oxide Synthase Type II
  • Ptgs2 protein, mouse
  • Cyclooxygenase 2
  • Phosphatidylinositol 3-Kinases
  • Extracellular Signal-Regulated MAP Kinases
  • p38 Mitogen-Activated Protein Kinases
  • Dinoprostone