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Research ArticleArticle

Anandamide Inhibits Nuclear Factor-κB Activation through a Cannabinoid Receptor-Independent Pathway

Rocı́o Sancho, Marco A. Calzado, Vincenzo Di Marzo, Giovanni Appendino and Eduardo Muñoz
Molecular Pharmacology February 2003, 63 (2) 429-438; DOI: https://doi.org/10.1124/mol.63.2.429
Rocı́o Sancho
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Marco A. Calzado
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Vincenzo Di Marzo
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Giovanni Appendino
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Eduardo Muñoz
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Abstract

Anandamide (arachidonoylethanolamine, AEA), an endogenous agonist for both the cannabinoid CB1 receptor and the vanilloid VR1 receptor, elicits neurobehavioral, anti-inflammatory, immunomodulatory, and proapoptotic effects. Because of the central role of nuclear factor-κB (NF-κB) in the inflammatory process and the immune response, we postulated that AEA might owe some of its effects to the suppression of NF-κB. This study shows that AEA inhibits tumor necrosis factor-α (TNFα)-induced NF-κB activation by direct inhibition of the IκB kinase (IKK)β and, to a lesser extent, the IKKα subunits of κB inhibitor (IκB) kinase complex, and that IKKs inhibition by AEA correlates with inhibition of IκBα degradation, NF-κB binding to DNA, and NF-κB-dependent transcription in TNFα-stimulated cells. AEA also prevents NF-κB-dependent reporter gene expression induced by mitogen-activated protein kinase kinase kinase and NF-κB-inducing kinase. The NF-κB inhibitory activity of AEA was independent of CB1 and CB2activation in TNFα-stimulated 5.1 and A549 cell lines, which do not express vanilloid receptor 1, and was not mediated by hydrolytic products formed through the activity of the enzyme fatty acid amide hydrolase. Chemical modification markedly affected AEA inhibitory activity on NF-κB, suggesting rather narrow structure-activity relationships and the specific interaction with a molecular target. Substitution of the alkyl moiety with less saturated fatty acids generally reduced or abolished activity. However, replacement of the ethanolamine “head” with a vanillyl group led to potent inhibition of TNFα-induced NF-κB-dependent transcription. These findings provide new mechanistic insights into the anti-inflammatory and proapoptotic activities of AEA, and should foster the synthesis of improved analogs amenable to pharmaceutical development as anti-inflammatory agents.

Footnotes

  • This work was supported by MCyT grant BIO 2000-1091-C01 (to E.M.), by European Union grant QLK3-CT-2000-00463 (to E.M. and G.A.), and by INTAS grant 97/1297 (to V.D.M.).

  • R. S. and M.A.C. contributed equally to this study.

  • Abbreviations:
    AEA
    anandamide
    2-AG
    2-arachidonoylglicerol
    CB
    cannabinoid receptor
    FAAH
    fatty acid amide hydrolase
    VR1
    vanilloid receptor type 1
    NF-κB
    nuclear factor-κB
    IκB
    κB inhibitor
    IKK
    IκB kinase
    IKC
    IκB kinase complex
    NIK
    NF-κB inducing kinase
    TNFα
    tumor necrosis factor-α
    MEKK
    mitogen-activated protein kinase kinase kinase
    COX-2
    cyclooxygenase 2
    HIV-LTR
    HIV long terminal repeat
    mAb
    monoclonal antibody
    ATFMK
    arachidonoyl trifluoromethyl ketone
    N-AVAM
    N-acylvanillamide
    DTT
    dithiothreitol
    NP-40
    Nonidet-P40
    EMSA
    electrophoretic mobility shift assay
    RT-PCR
    reverse transcriptase-polymerase chain reaction
    bp
    base pair(s)
    ERK
    extracellular signal-regulated kinase
    cyPG
    cyclopentenone prostaglandin
    SR141716A
    N-(piperidin-1-yl)-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboximide hydrochloride
    • Received June 5, 2002.
    • Accepted October 21, 2002.
  • The American Society for Pharmacology and Experimental Therapeutics
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Molecular Pharmacology: 63 (2)
Molecular Pharmacology
Vol. 63, Issue 2
1 Feb 2003
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Research ArticleArticle

Anandamide Inhibits Nuclear Factor-κB Activation through a Cannabinoid Receptor-Independent Pathway

Rocı́o Sancho, Marco A. Calzado, Vincenzo Di Marzo, Giovanni Appendino and Eduardo Muñoz
Molecular Pharmacology February 1, 2003, 63 (2) 429-438; DOI: https://doi.org/10.1124/mol.63.2.429

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Research ArticleArticle

Anandamide Inhibits Nuclear Factor-κB Activation through a Cannabinoid Receptor-Independent Pathway

Rocı́o Sancho, Marco A. Calzado, Vincenzo Di Marzo, Giovanni Appendino and Eduardo Muñoz
Molecular Pharmacology February 1, 2003, 63 (2) 429-438; DOI: https://doi.org/10.1124/mol.63.2.429
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