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Research ArticleInflammation, Immunopharmacology, and Asthma

Luteolin, a Novel Natural Inhibitor of Tumor Progression Locus 2 Serine/Threonine Kinase, Inhibits Tumor Necrosis Factor-α-Induced Cyclooxygenase-2 Expression in JB6 Mouse Epidermis Cells

Jong-Eun Kim, Joe Eun Son, Young Jin Jang, Dong Eun Lee, Nam Joo Kang, Sung Keun Jung, Yong-Seok Heo, Ki Won Lee and Hyong Joo Lee
Journal of Pharmacology and Experimental Therapeutics September 2011, 338 (3) 1013-1022; DOI: https://doi.org/10.1124/jpet.111.179200
Jong-Eun Kim
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Joe Eun Son
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Young Jin Jang
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Dong Eun Lee
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Nam Joo Kang
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Sung Keun Jung
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Yong-Seok Heo
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Ki Won Lee
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Hyong Joo Lee
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Abstract

Targeting tumor necrosis factor (TNF)-α-mediated signal pathways may be a promising strategy for developing chemopreventive agents, because TNF-α-mediated cyclooxygenase (COX)-2 expression plays a key role in inflammation and carcinogenesis. Luteolin [2-(3,4-dihydroxyphenyl)-5,7-dihydroxy-4-chromenone] exerts anticarcinogenic effects, although little is known about the underlying molecular mechanisms and specific targets of this compound. In the present study, we found that luteolin inhibited TNF-α-induced COX-2 expression by down-regulating the transactivation of nuclear factor-κB and activator protein-1. Furthermore, luteolin inhibited TNF-α-induced phosphorylation of mitogen-activated protein kinase/extracellular signal-regulated kinase (ERK) kinase 1/ERK/p90RSK, mitogen-activated protein kinase kinase 4/c-Jun N-terminal kinase/c-Jun, and Akt/p70S6K. However, it had no effect on the phosphorylation of p38. These effects of luteolin on TNF-α-mediated signaling pathways and COX-2 expression are similar to those achieved by blocking tumor progression locus 2 serine/threonine kinase (TPL2) using pharmacologic inhibitors and small interfering RNAs. Luteolin inhibited TPL2 activity in vitro and in TPL2 immunoprecipitation kinase assays by binding directly in an ATP-competitive manner. Overall, these results indicate that luteolin exerts potent chemopreventive activities, which primarily target TPL2.

Footnotes

  • This work was supported in part by the World Class University Program [Grant R31-2008-00-10056-0] and the National Leap Research Program [Grant 2010-0029233] through the National Research Foundation of Korea funded by the Ministry of Education, Science, and Technology, Republic of Korea.

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

    doi:10.1124/jpet.111.179200.

  • ABBREVIATIONS:

    TNF
    tumor necrosis factor
    TNFR
    TNF-α receptor
    TPL2
    tumor progression locus 2 serine/threonine kinase
    siTPL2
    small interfering TLP2
    TPL2i
    TPL2 inhibitor, 4-(3-chloro-4-fluorophenylamino)-6-(pyridin-3-yl-methylamino)-3-cyano-[1,7]-naphthyridine
    COX
    cyclooxygenase
    AP-1
    activator protein-1
    NF-κB
    nuclear factor-κB
    ERK
    extracellular signal-regulated kinase
    FBS
    fetal bovine serum
    JNK
    c-Jun N-terminal kinase
    MAPK
    mitogen-activated protein kinase
    MEK1
    MAPK/ERK kinase 1
    MKK4
    mitogen-activated protein kinase kinase 4
    MEM
    minimum essential medium
    MTT
    3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide
    G418
    (2R,3S,4R,5R,6S)-5-amino-6-[(1R,2S,3S,4R,6S)-4,6-diamino-3-[(2R,3R,4R,5R)-3,5-dihydroxy-5-methyl-4-methylaminooxan-2-yl]oxy-2-hydroxycyclohexyl]oxy-2-(1-hydroxyethyl)oxane-3,4-diol
    DTT
    dithiothreitol
    PMSF
    phenylmethylsulfonyl fluoride
    siRNA
    small interfering RNA
    siMock
    small interfering Mock.

  • Received January 13, 2011.
  • Accepted June 23, 2011.
  • Copyright © 2011 by The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 338 (3)
Journal of Pharmacology and Experimental Therapeutics
Vol. 338, Issue 3
1 Sep 2011
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Research ArticleInflammation, Immunopharmacology, and Asthma

Luteolin, a Novel Natural Inhibitor of Tumor Progression Locus 2 Serine/Threonine Kinase, Inhibits Tumor Necrosis Factor-α-Induced Cyclooxygenase-2 Expression in JB6 Mouse Epidermis Cells

Jong-Eun Kim, Joe Eun Son, Young Jin Jang, Dong Eun Lee, Nam Joo Kang, Sung Keun Jung, Yong-Seok Heo, Ki Won Lee and Hyong Joo Lee
Journal of Pharmacology and Experimental Therapeutics September 1, 2011, 338 (3) 1013-1022; DOI: https://doi.org/10.1124/jpet.111.179200

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Research ArticleInflammation, Immunopharmacology, and Asthma

Luteolin, a Novel Natural Inhibitor of Tumor Progression Locus 2 Serine/Threonine Kinase, Inhibits Tumor Necrosis Factor-α-Induced Cyclooxygenase-2 Expression in JB6 Mouse Epidermis Cells

Jong-Eun Kim, Joe Eun Son, Young Jin Jang, Dong Eun Lee, Nam Joo Kang, Sung Keun Jung, Yong-Seok Heo, Ki Won Lee and Hyong Joo Lee
Journal of Pharmacology and Experimental Therapeutics September 1, 2011, 338 (3) 1013-1022; DOI: https://doi.org/10.1124/jpet.111.179200
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