Nodakenin suppresses lipopolysaccharide-induced inflammatory responses in macrophage cells by inhibiting tumor necrosis factor receptor-associated factor 6 and nuclear factor-κB pathways and protects mice from lethal endotoxin shock.

Nodakenin, a coumarin isolated from the roots of Angelicae gigas, has been reported to possess neuroprotective, antiaggregatory, antibacterial, and memory-enhancing effects. In the present study, we investigated the anti-inflammatory effects of nodakenin by examining its in vitro inhibitory effects on inducible nitric-oxide synthase (iNOS), cyclooxygenase-2 (COX-2), and proinflammatory cytokines in lipopolysaccharide (LPS)-induced RAW 264.7 macrophages and mouse peritoneal macrophages and its in vivo effects on LPS-induced septic shock in mice. Our results indicate that nodakenin concentration-dependently inhibits iNOS and COX-2 at the protein, mRNA, and promoter binding levels, and these inhibitions cause attendant decreases in the production of nitric oxide (NO) and prostaglandin E₂ (PGE₂). Furthermore, we found that nodakenin inhibits the production and mRNA expression of tumor necrosis factor-α (TNF-α), interleukin (IL)-6, and IL-1β induced by LPS. Molecular data revealed that nodakenin suppressed the transcriptional activity and translocation of nuclear factor-κB (NF-κB) by inhibiting inhibitory κB-α degradation and IκB kinase-α/β phosphorylation. In addition, nodakenin was found to significantly inhibit the LPS-induced binding of transforming growth factor-β-activated kinase 1 to tumor necrosis factor receptor-associated factor 6 (TRAF6) by reducing TRAF6 ubiquitination. Pretreatment with nodakenin reduced the serum levels of NO, PGE₂, and proinflammatory cytokines and increased the survival rate of mice with LPS-induced endotoxemia. Taken together, our data suggest that nodakenin down-regulates the expression of the proinflammatory iNOS, COX-2, TNF-α, IL-6, and IL-1β genes in macrophages by interfering with the activation of TRAF6, thus preventing NF-κB activation.
AuthorsHong-Kun Rim, Woong Cho, Sang Hyun Sung, Kyung-Tae Lee
JournalThe Journal of pharmacology and experimental therapeutics (J Pharmacol Exp Ther) Vol. 342 Issue 3 Pg. 654-64 (Sep 2012) ISSN: 1521-0103 [Electronic] United States
PMID22637723 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
Chemical References
  • Anti-Inflammatory Agents
  • Coumarins
  • Glucosides
  • I-kappa B Proteins
  • Interleukin-1beta
  • Interleukin-6
  • Lipopolysaccharides
  • NF-kappa B
  • TNF Receptor-Associated Factor 6
  • Tumor Necrosis Factor-alpha
  • NF-kappaB inhibitor alpha
  • Nitric Oxide
  • nodakenin
  • Nitric Oxide Synthase Type II
  • Nos2 protein, mouse
  • Ptgs2 protein, mouse
  • Cyclooxygenase 2
  • I-kappa B Kinase
  • MAP Kinase Kinase Kinases
  • MAP kinase kinase kinase 7
  • Mitogen-Activated Protein Kinase Kinases
  • Dinoprostone
  • Animals
  • Anti-Inflammatory Agents (pharmacology)
  • Cells, Cultured
  • Coumarins (pharmacology)
  • Cyclooxygenase 2 (genetics, metabolism)
  • Dinoprostone (antagonists & inhibitors, genetics, metabolism)
  • Down-Regulation (drug effects, genetics)
  • Drug Interactions
  • Glucosides (pharmacology)
  • I-kappa B Kinase (antagonists & inhibitors, genetics, metabolism)
  • I-kappa B Proteins (antagonists & inhibitors, genetics, metabolism)
  • Inflammation (drug therapy, genetics, metabolism)
  • Interleukin-1beta (antagonists & inhibitors, genetics, metabolism)
  • Interleukin-6 (antagonists & inhibitors, genetics, metabolism)
  • Lipopolysaccharides (pharmacology)
  • MAP Kinase Kinase Kinases (genetics, metabolism)
  • Macrophages (drug effects, metabolism)
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mitogen-Activated Protein Kinase Kinases (antagonists & inhibitors, genetics, metabolism)
  • NF-kappa B (antagonists & inhibitors, genetics, metabolism)
  • Nitric Oxide (antagonists & inhibitors, genetics, metabolism)
  • Nitric Oxide Synthase Type II (antagonists & inhibitors, genetics, metabolism)
  • Phosphorylation (drug effects, genetics)
  • Promoter Regions, Genetic (drug effects)
  • Shock, Septic (drug therapy, metabolism, prevention & control)
  • Signal Transduction (drug effects, genetics)
  • TNF Receptor-Associated Factor 6 (antagonists & inhibitors, genetics, metabolism)
  • Transcription, Genetic (drug effects, genetics)
  • Tumor Necrosis Factor-alpha (antagonists & inhibitors, genetics, metabolism)
  • Ubiquitination (drug effects, genetics)

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