jte-907 and Colitis

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