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.

Abstract

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.

• Authors: Hong-Kun Rim, Woong Cho, Sang Hyun Sung, Kyung-Tae Lee
• Journal: The 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
• PMID: 22637723 (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
• Nfkbia protein, mouse
• TNF Receptor-Associated Factor 6
• Tumor Necrosis Factor-alpha
• NF-KappaB Inhibitor alpha
• Nitric Oxide
• 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
• nodakenin

Topics

• 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-KappaB Inhibitor alpha
• 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)