jte-907 and Inflammation

Cannabinoids are known to possess anti-inflammatory and immunomodulatory properties, but the mechanisms involved are not fully understood. CB2 is the cannabinoid receptor that is expressed primarily on hematopoietic cells and mediates the immunoregulatory functions of cannabinoids. In order to study the effect of JTE907, a selective/inverse agonist of CB2 with anti-inflammatory properties, on the differentiation of T cell subtypes, we used an in vitro system of Th lineage-specific differentiation of naïve CD4

Topics: Animals; Anti-Inflammatory Agents; Cell Differentiation; Colitis; Colon; Cytokines; Dioxoles; Disease Models, Animal; Inflammation; Inflammatory Bowel Diseases; Male; Mice, Inbred C57BL; Phenotype; Quinolones; Receptor, Cannabinoid, CB2; Spleen; T-Lymphocytes

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.

Topics: Arachidonic Acids; Biological Transport; Caco-2 Cells; Cannabinoid Receptor Agonists; Colitis; Colon; Colorectal Neoplasms; Dioxoles; Endocannabinoids; Epithelial Cells; Epithelium; Female; Humans; Hydrocortisone; Indoles; Inflammation; Interleukin-1beta; Intestinal Mucosa; Lymphocyte Count; Male; Permeability; Polyunsaturated Alkamides; Quinolones; Receptor, Cannabinoid, CB2; Tumor Necrosis Factor-alpha

Inflammation in adipose tissue is a characteristic of obesity and the metabolic syndrome. It is suggested that the endocannabinoid system is involved in the regulation of inflammatory and angiogenic processes within the tissue. Human subcutaneous preadipocytes (Zen Bio) were used as the source of human preadipocytes or adipocytes. Gene expression was examined by RT-PCR and real-time PCR. The secretion of inflammation-related proteins was determined by an ELISA array. In experiments on adipocytes treated at day 14 post-differentiation, JTE-907, a synthetic cannabinoid, upregulated the expression of key inflammatory markers - IL-6, MCP-1 and IL-1 beta - and angiogenic factors - VEGF and ANGPTL4 - at 10 microM after 20 h of treatment, having also increased the expression of TRPV1 at 10 microM. JTE-907 showed no effect after 4 h. The ELISA array showed a 2.6-fold increase in IL-6 protein release. The effect of JTE-907 was inhibited by AM251 (CB1 antagonist), and partially by arachidonyl serotonin (TRPV1 and FAAH antagonist). The CB2 antagonist, AM630, partially upregulated the effect of JTE-907. Preadipocytes fed 14 days after 100% confluence exhibited downregulation of CB1, MCP-1, and IL-1 beta, 20 h after having been exposed to JTE-907. CB1 and TRPV1 receptors participate in the regulation of several inflammatory and angiogenic factors in human adipocytes, indicating their potential value as targets for the treatment of disorders related to obesity.

Topics: Adipocytes; Biomarkers; Cannabinoid Receptor Antagonists; Cannabinoids; Cell Differentiation; Chemokine CCL2; Dioxoles; Female; Humans; Inflammation; Inflammation Mediators; Interleukin-1beta; Middle Aged; Neovascularization, Pathologic; Quinolones; Receptors, Cannabinoid; TRPV Cation Channels; Up-Regulation

Involvement of cannabinoid CB(2) receptor and effect of cannabinoid CB(2) receptor antagonist/inverse agonists on cutaneous inflammation were investigated. Mice ears topically exposed to an ether-linked analogue of 2-arachidonoylglycerol (2-AG-E) or selective cannabinoid CB(2) receptor agonist, {4-[4-(1,1-dimethylheptyl)-2,6-dimethoxy-phenyl]-6.6-dimethyl-bicyclo[3.1.1]hept-2-en-2-yl}-methanol (HU-308), had early and late ear swelling (0--24 h and 1--8 days after exposure, respectively). Both types of responses induced by 2-AG-E were significantly suppressed by oral administration of cannabinoid CB(2) receptor antagonist/inverse agonists, [N-(benzo[1,3]dioxol-5-ylmethyl)-7-methoxy-2-oxo-8-pentyloxy-1,2-dihydroquinoline-3-carboxamide] (JTE-907) and {N-[(1S)-endo-1,3,3-trimethylbicyclo[2.2.1]heptan-2 yl]5-(4-chloro-3-methyl-phenyl)-1-(4-methylbenzyl)pyrazole-3-carboxamide}} (SR 144528). In contrast, JTE-907 did not affect arachidonic acid-induced swelling. Orally administered JTE-907 (0.1-10 mg/kg) and SR 144528 (1 mg/kg) also produced significant inhibition of dinitrofluorobenzene-induced ear swelling, with increased cannabinoid CB(2) receptor mRNA expression observed in the inflamed ear. These results suggest that cannabinoid CB(2) receptor is partially involved in local inflammatory responses and cannabinoid CB(2) receptor antagonist/inverse agonist has beneficial effects on ear swelling.

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Arachidonic Acid; Area Under Curve; Camphanes; Cannabinoids; Dinitrofluorobenzene; Dioxoles; Disease Models, Animal; Drug Eruptions; Ear, External; Female; Indomethacin; Inflammation; Lymph Nodes; Mice; Mice, Inbred BALB C; Pyrazoles; Quinolones; Receptor, Cannabinoid, CB2; RNA, Messenger; Time Factors