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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.
J Pharmacol Exp Ther 2012; 342(3):654-64JP

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+Show Affiliations

Department of Pharmaceutical Biochemistry, College of Pharmacy, Kyung Hee University, Seoul, Republic of Korea.No affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

22637723

Citation

Rim, Hong-Kun, et al. "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." The Journal of Pharmacology and Experimental Therapeutics, vol. 342, no. 3, 2012, pp. 654-64.
Rim HK, Cho W, Sung SH, et al. 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. J Pharmacol Exp Ther. 2012;342(3):654-64.
Rim, H. K., Cho, W., Sung, S. H., & Lee, K. T. (2012). 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. The Journal of Pharmacology and Experimental Therapeutics, 342(3), pp. 654-64. doi:10.1124/jpet.112.194613.
Rim HK, et al. 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. J Pharmacol Exp Ther. 2012;342(3):654-64. PubMed PMID: 22637723.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - 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. AU - Rim,Hong-Kun, AU - Cho,Woong, AU - Sung,Sang Hyun, AU - Lee,Kyung-Tae, Y1 - 2012/05/25/ PY - 2012/5/29/entrez PY - 2012/5/29/pubmed PY - 2013/3/8/medline SP - 654 EP - 64 JF - The Journal of pharmacology and experimental therapeutics JO - J. Pharmacol. Exp. Ther. VL - 342 IS - 3 N2 - 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. SN - 1521-0103 UR - https://www.unboundmedicine.com/medline/citation/22637723/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_ L2 - http://jpet.aspetjournals.org/cgi/pmidlookup?view=long&pmid=22637723 DB - PRIME DP - Unbound Medicine ER -