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Research ArticleInflammation, Immunopharmacology, and Asthma

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

Hong-Kun Rim, Woong Cho, Sang Hyun Sung and Kyung-Tae Lee
Journal of Pharmacology and Experimental Therapeutics September 2012, 342 (3) 654-664; DOI: https://doi.org/10.1124/jpet.112.194613
Hong-Kun Rim
Departments of Pharmaceutical Biochemistry (H.-K.R., W.C., K.-T.L.) and Life and Nanopharmaceutical Science (W.C., K.-T.L.), College of Pharmacy, and Department of Biommedical Science, College of Medical Science (H.-K.R., K.-T.L.), Kyung Hee University, Seoul, Republic of Korea; and College of Pharmacy, Seoul National University, Seoul, Republic of Korea (S.H.S.)
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Woong Cho
Departments of Pharmaceutical Biochemistry (H.-K.R., W.C., K.-T.L.) and Life and Nanopharmaceutical Science (W.C., K.-T.L.), College of Pharmacy, and Department of Biommedical Science, College of Medical Science (H.-K.R., K.-T.L.), Kyung Hee University, Seoul, Republic of Korea; and College of Pharmacy, Seoul National University, Seoul, Republic of Korea (S.H.S.)
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Sang Hyun Sung
Departments of Pharmaceutical Biochemistry (H.-K.R., W.C., K.-T.L.) and Life and Nanopharmaceutical Science (W.C., K.-T.L.), College of Pharmacy, and Department of Biommedical Science, College of Medical Science (H.-K.R., K.-T.L.), Kyung Hee University, Seoul, Republic of Korea; and College of Pharmacy, Seoul National University, Seoul, Republic of Korea (S.H.S.)
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Kyung-Tae Lee
Departments of Pharmaceutical Biochemistry (H.-K.R., W.C., K.-T.L.) and Life and Nanopharmaceutical Science (W.C., K.-T.L.), College of Pharmacy, and Department of Biommedical Science, College of Medical Science (H.-K.R., K.-T.L.), Kyung Hee University, Seoul, Republic of Korea; and College of Pharmacy, Seoul National University, Seoul, Republic of Korea (S.H.S.)
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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.

Footnotes

  • This research was supported by the Basic Science Research Program through the National Research Foundation of Korea, which is funded by the Korean government [Grants 2011-0023407, 2011-0030724].

  • Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.

    http://dx.doi.org/10.1124/jpet.112.194613.

  • ABBREVIATIONS:

    LPS
    lipopolysaccharide
    AP-1
    activator protein-1
    Con
    control
    COX
    cyclooxygenase
    DMEM
    Dulbecco's modified Eagle's medium
    ELISA
    enzyme-linked immunosorbent assay
    ERK
    extracellular signal-related kinase
    IκB
    inhibitor of κB
    IKK
    IκB kinase
    IL
    interleukin
    IRAK1
    IL-1 receptor-associated kinase 1
    JNK
    c-Jun N-terminal kinase
    l-NIL
    l-N6-(1-iminoethyl) lysine
    MAPK
    mitogen-activated protein kinase
    MTT
    3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide
    NF-κB
    nuclear factor-κB
    NO
    nitric oxide
    NOS
    NO synthase
    iNOS
    inducible NOS
    p-
    phosphorylated
    NS398
    N-(2-cyclohexyloxy-4-nitrophenyl)methanesulfonamide
    PARP
    poly(ADP-ribose) polymerase
    PBS
    phosphate-buffered saline
    PCR
    polymerase chain reaction
    PG
    prostaglandin
    RT
    reverse transcriptase
    TAK1
    transforming growth factor-β-activated kinase 1
    TNF-α
    tumor necrosis factor-α
    TRAF6
    tumor necrosis factor receptor-associated factor 6
    Ub
    ubiquitin
    Ubc
    Ub-conjugating enzyme complex.

  • Received March 20, 2012.
  • Accepted May 24, 2012.
  • Copyright © 2012 by The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 342 (3)
Journal of Pharmacology and Experimental Therapeutics
Vol. 342, Issue 3
1 Sep 2012
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Research ArticleInflammation, Immunopharmacology, and Asthma

Nodakenin Suppresses LPS-Induced Inflammatory Responses

Hong-Kun Rim, Woong Cho, Sang Hyun Sung and Kyung-Tae Lee
Journal of Pharmacology and Experimental Therapeutics September 1, 2012, 342 (3) 654-664; DOI: https://doi.org/10.1124/jpet.112.194613

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Research ArticleInflammation, Immunopharmacology, and Asthma

Nodakenin Suppresses LPS-Induced Inflammatory Responses

Hong-Kun Rim, Woong Cho, Sang Hyun Sung and Kyung-Tae Lee
Journal of Pharmacology and Experimental Therapeutics September 1, 2012, 342 (3) 654-664; DOI: https://doi.org/10.1124/jpet.112.194613
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