title: Inhibition of interleukin-8 release in the human colonic epithelial cell line HT-29 by cannabinoids.
abstract: We have investigated the effects of cannabinoid agonists and antagonists on tumour necrosis factor-alpha (TNF-alpha)-induced secretion of interleukin-8 from the colonic epithelial cell line, HT-29. The cannabinoid receptor agonists [(-)-3-[2-hydroxy-4-(1,1-dimethyl-heptyl)-phenyl]4-[3-hydroxypropyl]cyclo-hexan-1-ol] (CP55,940); Delta-9-tetrahydrocannabinol; [R(+)-[2,3-dihydro-5-methyl-3-[(morpholinyl) methyl] pyrrolo[1,2,3-de]1,4-benzoxazin-6-yl](1-naphthyl) methanone mesylate] (WIN55,212-2) and 1-propyl-2-methyl-3-naphthoyl-indole (JWH 015) inhibited TNF-alpha induced release of interleukin-8 in a concentration-dependent manner. The less active enantiomer of WIN55212-2, [S(-)-[2,3-dihydro-5-methyl-3-[(morpholinyl)methyl]pyrrolo[1,2,3-de]1,4-benzoxazin-6-yl](1-naphthyl) methanone mesylate (WIN55212-3), and the cannabinoid CB(1) receptor agonist arachidonoyl-2-chloroethylamide (ACEA) had no significant effect on TNF-alpha-induced release of interleukin-8. The cannabinoid CB(1) receptor antagonist N-(piperidin-1-yl)-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1,4-pyrazole-3-carboxamide hydrochloride (SR141716A; 10(-6) M) antagonised the inhibitory effect of CP55,940 (pA(2)=8.3+/-0.2, n=6) but did not antagonise the inhibitory effects of WIN55212-2 and JWH 015. The cannabinoid CB(2) receptor antagonist N-(1,S)-endo1,3,3-trimethylbicyclo(2,2,1)heptan-2-yl)-5(4-chloro-3-methyl-phenyl)-1-(4-methylbenzyl)-pyrazole-3-carboxamide (SR144528; 10(-6) M) antagonised the inhibitory effects of CP55,940 (pA(2)=8.2+/-0.8, n=6), WIN55212-2 (pA(2)=7.1+/-0.3, n=6) and JWH 015 (pA(2)=7.6+/-0.3, n=6), respectively. Western immunoblotting of HT-29 cell lysates revealed a protein with a size that is consistent with the presence of cannabinoid CB(2) receptors. We conclude that in HT-29 cells, TNF-alpha-induced interleukin-8 release is inhibited by cannabinoids through activation of cannabinoid CB(2) receptors.
authors.affiliation: Department of Biosciences, CP Snow Building, University of Hertfordshire, Hatfield Campus, College Lane, Hertfordshire AL10 9AB, Hatfield, UK.
authors.forename: Kenneth
authors.initials: K
authors.lastname: Ihenetu
authors.forename: Areles
authors.initials: A
authors.lastname: Molleman
authors.forename: Mike E
authors.initials: ME
authors.lastname: Parsons
authors.forename: Clifford J
authors.initials: CJ
authors.lastname: Whelan
mesh_terms: D001095:Arachidonic Acids / Q000494:pharmacology; D048588:Benzoxazines; D001892:Camphanes / Q000494:pharmacology; D002186:Cannabinoids / Q000494:pharmacology*; D002470:Cell Survival / Q000187:drug effects; D003511:Cyclohexanols / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D019073:HT29 Cells / Q000187:drug effects* / Q000378:metabolism; D006801:Humans; D015151:Immunoblotting; D007211:Indoles / Q000494:pharmacology; D016209:Interleukin-8 / Q000378:metabolism*; D007700:Kinetics; D009025:Morpholines / Q000494:pharmacology; D009281:Naphthalenes / Q000494:pharmacology; D010880:Piperidines / Q000494:pharmacology; D011720:Pyrazoles / Q000494:pharmacology; D043882:Receptors, Cannabinoid; D011955:Receptors, Drug / Q000819:agonists / Q000037:antagonists & inhibitors / Q000378:metabolism; D000077285:Rimonabant; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology
chemical_list: D001095:Arachidonic Acids; D048588:Benzoxazines; D001892:Camphanes; D002186:Cannabinoids; D003511:Cyclohexanols; D007211:Indoles; D016209:Interleukin-8; D009025:Morpholines; D009281:Naphthalenes; D010880:Piperidines; D011720:Pyrazoles; D043882:Receptors, Cannabinoid; D011955:Receptors, Drug; C110630:SR 144528; D014409:Tumor Necrosis Factor-alpha; C119325:arachidonyl-2-chloroethylamide; C070417:(3R)-((2,3-dihydro-5-methyl-3-((4-morpholinyl)methyl)pyrrolo-(1,2,3-de)-1,4-benzoxazin-6-yl)(1-naphthalenyl))methanone; C054649:3-(2-hydroxy-4-(1,1-dimethylheptyl)phenyl)-4-(3-hydroxypropyl)cyclohexanol; D000077285:Rimonabant; C402944:JHW 015