Cannabinoid receptor-2 (CB2) agonist ameliorates colitis in IL-10−/− mice by attenuating the activation of T cells and promoting their apoptosis

Abstract

Inflammatory bowel disease (IBD) is a chronic intestinal inflammation caused by hyperactivated effector immune cells that produce pro-inflammatory cytokines. Recent studies have shown that the cannabinoid system may play a critical role in mediating protection against intestinal inflammation. However, the effect of cannabinoid receptors induction after chronic colitis progression has not been investigated. Here, we investigate the effect of cannabinoid receptor-2 (CB2) agonist, JWH-133, after chronic colitis in IL-10−/− mice. JWH-133 effectively attenuated the overall clinical score, reversed colitis-associated pathogenesis and decrease in body weight in IL-10−/− mice. After JWH-133 treatment, the percentage of CD4+ T cells, neutrophils, mast cells, natural killer (NK1.1) cells, and activated T cells in the LP of colitis mice declined after JWH-133 treatment in the intestinal lamina propria (LP) and mesenteric lymph nodes (MLN). JWH-133 was also effective in ameliorating dextran sodium sulphate (DSS)-induced colitis. In this model, JWH-133 reduced the number and percentage of macrophages and IFN-γ expressing cells that were induced during colitis progression. Treatment with aminoalkylindole 6-iodopravadoline (AM630), a CB2 receptor antagonist, reversed the colitis protection provided by JWH-133 treatment. Also, activated T cells were found to undergo apoptosis following JWH-133 treatment both in-vivo and in-vitro. These findings suggest that JWH-133 mediates its effect through CB2 receptors, and ameliorates chronic colitis by inducing apoptosis in activated T cells, reducing the numbers of activated T cells, suppressing induction of mast cells, NK cells, and neutrophils at sites of inflammation in the LP. These results support the idea that the CB2 receptor agonists may serve as a therapeutic modality against IBD.

The endocannabinoid system in inflammatory bowel diseases: from pathophysiology to therapeutic opportunity

“…The reduction in cellular infiltrates in JWH-133-treated mice was further confirmed with isolated cells from the LP and MLN of DSSmice. CD11b + cells were increased in the LP and MLN of untreated mice -consistent with the macrophage-induced inflammation characteristic of DSS -and reduced following JWH-133 treatment [36]. A similar effect was observed for INF-g + cells [36], consistent with the fact that INF-g plays a critical role in colitis induction and progression.…”

“…[64], and spontaneous colitis in IL-10 À/À mice (2.5 mg/kg, q.a.d.) [36]. In all of these models, CB 2 activation led to improved macroscopic as well as histological colon alterations and reduced cellular infiltrates.…”

“…The effects of both agonists were confirmed to be CB 2 -mediated because they were reversed in the presence of AM630 (10 mg/kg or 20 mg/kg, q.d.) and absent in CB 2 À/À mice [36,61]. In one study, AM630 seemed to exacerbate TNBS-induced colitis [61], but this was not consistent over all measured parameters and was not confirmed by two other studies using AM630 in studies of TNBS-induced and DSS-induced colitis [57,65].…”

“…Indeed, cannabinoids such as anandamide, noladin ether, and arachidonoylcyclopropylamide (ACPA) induce wound-closure in human colonic epithelial cell lines, suggesting that delayed wound healing, a feature of IBD lesions, might be reversed by cannabinoids [34]. Additionally, in vitro studies suggest roles for both cannabinoid receptors in modulating inflammatory processes, including suppression of the activation of macrophages and mast cells, secretion of proinflammatory cytokines, and modulation of T helper lymphocytes by reducing the activated T cell population, inducing their apoptosis, and inhibiting their proliferation [33,[35][36][37][38][39][40].…”

“…JWH-133, a CB 2 -selective agonist, effectively reduces inflammation at the stated doses in DSS-induced colitis (10 mg/kg or 20 mg/kg, b.i.d.) [36,64], TNBS-induced colitis (20 mg/kg, q.d. or b.i.d.)…”