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The molecular events mediating the immunomodulatory properties of cannabinoids have remained largely unresolved. We have therefore investigated the molecular mechanism(s) through which R-(+)-[2,3-dihydro-5-methyl-3-[(morpholinyl)methyl] pyrrolo[1,2,3-de]-1,4-benzoxazinyl]-(1-napthanlenyl) methanone (WIN55212-2) modulate production of interleukin-8 (IL-8) in HT-29 cells. Release of IL-8 induced by tumor necrosis factor-alpha (TNF-alpha) was determined by enzyme-linked immunosorbent assay (ELISA). Changes in expression of inhibitory kappa B (IkappaB) were monitored by Western blotting and activation of nuclear factor-kappa B (NF-kappaB) was determined in electrophoretic mobility shift assay (EMSAs). TNF-alpha induced release of IL-8 was inhibited by WIN55212-2 which also blocked the degradation of IkappaB-alpha and activation of NF-kappaB induced by TNF-alpha. These data provide strong evidence that WIN55212-2 may modulate IL-8 release by negatively regulating the signaling cascade leading to the activation of NF-kappaB. These findings highlight a potential mechanism for the immunomodulatory properties of cannabinoids and contribute towards acquiring a clear understanding of the role of cannabinoids in inflammation.

Original publication

DOI

10.1016/j.ejphar.2006.04.015

Type

Journal article

Journal

Eur J Pharmacol

Publication Date

01/07/2006

Volume

540

Pages

183 - 190

Keywords

Benzoxazines, Blotting, Western, Cannabinoid Receptor Agonists, Cannabinoids, Cycloheximide, Cysteine Proteinase Inhibitors, Dactinomycin, Dose-Response Relationship, Drug, Enzyme-Linked Immunosorbent Assay, HT29 Cells, Humans, I-kappa B Proteins, Interleukin-8, Leupeptins, Morpholines, NF-kappa B, Naphthalenes, Protein Synthesis Inhibitors, Receptors, Cannabinoid, Signal Transduction, Tumor Necrosis Factor-alpha, Up-Regulation