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Vol. 63, Issue 2, 429-438, February 2003
B Activation through a
Cannabinoid Receptor-Independent Pathway
Departamento de Biología Celular, Fisiología e
Inmunología, Universidad de Córdoba, Facultad de
Medicina, Córdoba, Spain (R.S., M.A.C., E.M.); Endocannabinoid
Research Group, Instituto di Chimica Biomolecolare, Consiglio Nazionale
delle Ricerche, Pozzuoli (Napoli), Italy (V.D.); and Dipartimento di
Scienze Chimiche Alimentari Farmaceutiche e Farmacologiche, Novara,
Italy (G.A.)
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-
B (NF-B) in the inflammatory process and the immune
response, we postulated that AEA might owe some of its effects to the
suppression of NF-B. This study shows that AEA inhibits tumor
necrosis factor-
(TNF)-induced NF-B activation by direct
inhibition of the IB kinase (IKK)
and, to a lesser extent, the
IKK subunits of B inhibitor (IB) kinase complex, and that IKKs
inhibition by AEA correlates with inhibition of IB degradation,
NF-B binding to DNA, and NF-B-dependent transcription in
TNF-stimulated cells. AEA also prevents NF-B-dependent reporter
gene expression induced by mitogen-activated protein kinase kinase
kinase and NF-B-inducing kinase. The NF-B inhibitory
activity of AEA was independent of CB1 and CB2
activation in TNF-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-B, 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 TNF-induced NF-B-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.
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