title: Cannabinoid CB2 receptor activation attenuates cytokine-evoked mucosal damage in a human colonic explant model without changing epithelial permeability.
abstract: Cannabinoid receptor activation is protective in animal colitis models. We sought to investigate if cannabinoids attenuated colitis-like tissue damage in human colonic specimens, with the hypothesis that cannabinoids would be protective in a cytokine-driven model of human colonic mucosal damage. Healthy human colonic mucosa was incubated with pro-inflammatory cytokines TNF-α and IL-1β to elicit colitis-like tissue damage. The cytokine-driven increase in scored crypt and mucosal damage and lymphocyte density was attenuated with concomitant hydrocortisone pretreatment. The cannabinoid receptor 2 (CB2) receptor-selective agonist JWH-015 significantly reduced colitis scores following cytokine incubation, as evidenced by a reduction in mucosal crypt and luminal epithelial damage and lymphocyte density in the lamina propria. The effect of JWH-015 was reversed in the presence of the CB2 receptor inverse agonist JTE-907. Anandamide was also protective in the cytokine-incubated explant colitis model in a manner reversible with JTE-907, while CB1 receptor agonism with ACEA was without effect. TNF-α and IL-1β together evoked an increase in paracellular epithelial permeability in Caco-2 cell monolayers over 48h of incubation. However, neither CB2 nor CB1 receptor activation altered the cytokine-evoked increase in permeability. These findings support a discrete role for CB2 receptors in the attenuation of detrimental pro-inflammatory cytokine-mediated mucosal damage in the human colon without directly affecting mucosal epithelial barrier function.
authors.affiliation: Discipline of Pharmacology, School of Medical Sciences, Faculty of Health Sciences, The University of Adelaide, South Australia, Australia.
authors.forename: B S
authors.initials: BS
authors.lastname: Harvey
authors.forename: L L
authors.initials: LL
authors.lastname: Nicotra
authors.forename: M
authors.initials: M
authors.lastname: Vu
authors.forename: S D
authors.initials: SD
authors.lastname: Smid
mesh_terms: D001095:Arachidonic Acids / Q000494:pharmacology; D001692:Biological Transport / Q000187:drug effects*; D018938:Caco-2 Cells; D063386:Cannabinoid Receptor Agonists / Q000494:pharmacology; D003092:Colitis / Q000188:drug therapy / Q000276:immunology / Q000378:metabolism*; D003106:Colon; D015179:Colorectal Neoplasms; D004149:Dioxoles / Q000494:pharmacology; D063388:Endocannabinoids / Q000494:pharmacology; D004847:Epithelial Cells / Q000378:metabolism; D004848:Epithelium / Q000187:drug effects / Q000378:metabolism; D005260:Female; D006801:Humans; D006854:Hydrocortisone / Q000494:pharmacology; D007211:Indoles / Q000494:pharmacology; D007249:Inflammation / Q000188:drug therapy / Q000276:immunology / Q000378:metabolism; D053583:Interleukin-1beta / Q000378:metabolism; D007413:Intestinal Mucosa / Q000187:drug effects*; D018655:Lymphocyte Count; D008297:Male; D010539:Permeability / Q000187:drug effects*; D053284:Polyunsaturated Alkamides / Q000494:pharmacology; D015363:Quinolones / Q000494:pharmacology; D043885:Receptor, Cannabinoid, CB2 / Q000819:agonists / Q000378:metabolism*; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
chemical_list: D001095:Arachidonic Acids; D063386:Cannabinoid Receptor Agonists; D004149:Dioxoles; D063388:Endocannabinoids; D007211:Indoles; D053583:Interleukin-1beta; C422645:JTE 907; D053284:Polyunsaturated Alkamides; D015363:Quinolones; D043885:Receptor, Cannabinoid, CB2; D014409:Tumor Necrosis Factor-alpha; C078814:anandamide; C402944:JHW 015; D006854:Hydrocortisone