title: β-Caryophyllene inhibits dextran sulfate sodium-induced colitis in mice through CB2 receptor activation and PPARγ pathway.
abstract: Cannabinoid receptor 2 (CB2) activation is suggested to trigger the peroxisome proliferator-activated receptor-γ (PPARγ) pathway, and agonists of both receptors improve colitis. Recently, the plant metabolite (E)-β-caryophyllene (BCP) was shown to bind to and activate CB2. In this study, we examined the anti-inflammatory effect of BCP in dextran sulfate sodium (DSS)-induced colitis and analyzed whether this effect was mediated by CB2 and PPARγ. Oral treatment with BCP reduced disease activity, colonic macro- and microscopic damage, myeloperoxidase and N-acetylglucosaminidase activities, and levels and mRNA expression of colonic tumor necrosis factor-α, IL-1β, interferon-γ, and keratinocyte-derived chemokine. BCP treatment also inhibited the activation of extracellular signal-regulated kinase 1/2, nuclear factor κB, IκB-kinase α/β, cAMP response element binding and the expression of caspase-3 and Ki-67. Moreover, BCP enhanced IL-4 levels and forkhead box P3 mRNA expression in the mouse colon and reduced cytokine levels (tumor necrosis factor-α, keratinocyte-derived chemokine, and macrophage-inflammatory protein-2) in a culture of macrophages stimulated with lipopolysaccharide. The use of the CB2 antagonist AM630 or the PPARγ antagonist GW9662 significantly reversed the protective effect of BCP. Confirming our results, AM630 reversed the beneficial effect of BCP on pro-inflammatory cytokine expression in IEC-6 cells. These results demonstrate that the anti-inflammatory effect of BCP involves CB2 and the PPARγ pathway and suggest BCP as a possible therapy for the treatment of inflammatory bowel disease.
authors.affiliation: Department of Pharmacology, Biological Sciences Center, Federal University of Santa Catarina Florianópolis, Santa Catarina, Brazil.
authors.forename: Allisson Freire
authors.initials: AF
authors.lastname: Bento
authors.forename: Rodrigo
authors.initials: R
authors.lastname: Marcon
authors.forename: Rafael Cypriano
authors.initials: RC
authors.lastname: Dutra
authors.forename: Rafaela Franco
authors.initials: RF
authors.lastname: Claudino
authors.forename: Maíra
authors.initials: M
authors.lastname: Cola
authors.forename: Daniela Ferraz Pereira
authors.initials: DF
authors.lastname: Leite
authors.forename: João B
authors.initials: JB
authors.lastname: Calixto
mesh_terms: D000818:Animals; D053148:Caspase 3 / Q000378:metabolism; D061945:Caspase Inhibitors; D062506:Claudin-4; D003092:Colitis / Q000139:chemically induced / Q000378:metabolism* / Q000517:prevention & control*; D003106:Colon / Q000187:drug effects / Q000201:enzymology / Q000473:pathology; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism; D016207:Cytokines / Q000378:metabolism; D016264:Dextran Sulfate; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D051550:I-kappa B Kinase / Q000378:metabolism; D018836:Inflammation Mediators / Q000378:metabolism; D019394:Ki-67 Antigen / Q000378:metabolism; D008070:Lipopolysaccharides / Q000494:pharmacology; D008262:Macrophage Activation / Q000187:drug effects; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism; D008565:Membrane Proteins / Q000378:metabolism; D051379:Mice; D016328:NF-kappa B / Q000378:metabolism; D010081:Oxazolone; D047495:PPAR gamma / Q000037:antagonists & inhibitors / Q000378:metabolism*; D000081223:Polycyclic Sesquiterpenes; D043885:Receptor, Cannabinoid, CB2 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D012717:Sesquiterpenes / Q000494:pharmacology*; D015398:Signal Transduction / Q000187:drug effects*
chemical_list: D061945:Caspase Inhibitors; D062506:Claudin-4; C568158:Cldn4 protein, mouse; C492004:Creb1 protein, mouse; D017362:Cyclic AMP Response Element-Binding Protein; D016207:Cytokines; D018836:Inflammation Mediators; D019394:Ki-67 Antigen; D008070:Lipopolysaccharides; D008565:Membrane Proteins; D016328:NF-kappa B; D047495:PPAR gamma; D000081223:Polycyclic Sesquiterpenes; D043885:Receptor, Cannabinoid, CB2; D012717:Sesquiterpenes; D010081:Oxazolone; D016264:Dextran Sulfate; C024714:caryophyllene; D051550:I-kappa B Kinase; D048049:Extracellular Signal-Regulated MAP Kinases; D053148:Caspase 3