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Tanshinone IIA inhibits LPS-induced NF-kappaB activation in RAW 264.7 cells: possible involvement of the NIK-IKK, ERK1/2, p38 and JNK pathways.

Abstract
Nuclear factor kappaB (NF-kappaB) activation by NF-kappaB-inducing kinase (NIK)-IkappaB alpha kinase (IKK) pathway and mitogen-activated protein kinases (MAPKs) pathway are important in inflammation. We recently found that the tanshinone IIA, a diterpene isolated from Salvia miltiorrhiza (S. miltiorrhiza), reduced the production of pro-inflammatory mediators in RAW 264.7 cells stimulated with lipopolysaccharide (LPS). However, little is known about the inhibitory mechanisms of tanshinone IIA on the production of pro-inflammatory mediators. To investigate the inhibitory mechanism, we determined the inhibitory effects of tanshinone IIA on the activation of NF-kappaB and IkappaB alpha phosphorylation, and also examined phosphorylation of NIK and IKK as well as the activation of MAPKs such as p38 MAPK (p38), extracellular signal-regulated kinases 1/2 (ERK1/2), and c-Jun N-terminal kinase (JNK) in RAW 264.7 cells stimulated with LPS. Tanshinone IIA inhibited NF-kappaB-DNA complex, NF-kappaB binding activity, and the phosphorylation of IkappaB alpha in a dose dependent manner. Tanshinone IIA also inhibited the translocation of NF-kappaB from cytosol to nucleus. Moreover, the phosphorylation of NIK and IKK as well as the phosphorylation of p38, ERK1/2, and JNK in the LPS-stimulated RAW 264.7 cells were suppressed by the tanshinone IIA in a dose dependent manner. These results suggest that tanshinone IIA may inhibit LPS-induced IkappaB alpha degradation and NF-kappaB activation via suppression of the NIK-IKK pathway as well as the MAPKs (p38, ERK1/2, and JNK) pathway in RAW 264.7 cells and these properties may provide a potential mechanism that explains the anti-inflammatory activity of tanshinone IIA.
AuthorsSeon Il Jang, Hyung Jin Kim, Young-Jun Kim, Seung-Il Jeong, Yong-Ouk You
JournalEuropean journal of pharmacology (Eur J Pharmacol) Vol. 542 Issue 1-3 Pg. 1-7 (Aug 07 2006) ISSN: 0014-2999 [Print] Netherlands
PMID16797002 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
Chemical References
  • Abietanes
  • Lipopolysaccharides
  • NF-kappa B
  • Phenanthrenes
  • tanshinone
  • Protein Serine-Threonine Kinases
  • I-kappa B Kinase
  • JNK Mitogen-Activated Protein Kinases
  • Mitogen-Activated Protein Kinase 1
  • Mitogen-Activated Protein Kinase 3
  • Mitogen-Activated Protein Kinases
  • p38 Mitogen-Activated Protein Kinases
  • NF-kappa B kinase
Topics
  • Abietanes
  • Animals
  • Cell Line
  • Dose-Response Relationship, Drug
  • Enzyme Activation (drug effects)
  • I-kappa B Kinase (metabolism)
  • JNK Mitogen-Activated Protein Kinases (metabolism)
  • Lipopolysaccharides (pharmacology)
  • Macrophages (cytology, drug effects, metabolism)
  • Mitogen-Activated Protein Kinase 1 (metabolism)
  • Mitogen-Activated Protein Kinase 3 (metabolism)
  • Mitogen-Activated Protein Kinases (metabolism)
  • Molecular Structure
  • NF-kappa B (metabolism)
  • Phenanthrenes (chemistry, pharmacology)
  • Phosphorylation (drug effects)
  • Protein Serine-Threonine Kinases (metabolism)
  • Signal Transduction (drug effects)
  • p38 Mitogen-Activated Protein Kinases (metabolism)

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