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 receptor 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, and 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 declined in the intestinal lamina propria (LP) and mesenteric lymph nodes (MLN) of mice with chronic colitis. JWH-133 was also effective in ameliorating dextran sodium sulfate (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-iodo-pravadoline (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, and 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.

• Authors: Udai P Singh, Narendra P Singh, Balwan Singh, Robert L Price, Mitzi Nagarkatti, Prakash S Nagarkatti
• Journal: Toxicology and applied pharmacology (Toxicol Appl Pharmacol) Vol. 258 Issue 2 Pg. 256-67 (Jan 15 2012) ISSN: 1096-0333 [Electronic] United States
• PMID: 22119709 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)
• Copyright: Published by Elsevier Inc.

Chemical References

• Cannabinoids
• Receptor, Cannabinoid, CB2
• Interleukin-10
• Dextran Sulfate
• 1,1-dimethylbutyl-1-deoxy-Delta(9)-THC

Topics

• Animals
• Apoptosis (drug effects)
• Body Weight (drug effects)
• Cannabinoids (pharmacology)
• Chronic Disease
• Colitis (drug therapy, physiopathology)
• Dextran Sulfate (toxicity)
• Disease Models, Animal
• Disease Progression
• Female
• Interleukin-10 (genetics)
• Killer Cells, Natural (drug effects, metabolism)
• Mast Cells (drug effects, metabolism)
• Mice
• Mice, Inbred C57BL
• Mice, Knockout
• Neutrophils (drug effects, metabolism)
• Receptor, Cannabinoid, CB2 (agonists)
• T-Lymphocytes (drug effects, metabolism)