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J Crohns Colitis. 2017 Oct 27;11(11):1369-1380. doi: 10.1093/ecco-jcc/jjx096.

Cannabinoid Receptor-2 Ameliorates Inflammation in Murine Model of Crohn's Disease.

Author information

1
Children's Hospital Colorado, Digestive Health Institute, Aurora, CO, USA.
2
Department of Pediatrics, University of Colorado School of Medicine, Aurora, CO, USA.
3
Children's Hospital Colorado, Department of Pathology, Aurora, CO, USA.
4
Department of Pathology, University of Colorado School of Medicine, Aurora, CO, USA.
5
Department of Medicine, University of Colorado School of Medicine, Aurora, CO, USA.
6
National Institutes of Health, National Institute on Aging, Bethesda, MD, USA.
7
Department of Internal Medicine I, Medical University of Tübingen, Tübingen, Germany.
8
Pulmonary Sciences and Critical Care Medicine, University of Colorado School of Medicine, Aurora, CO, USA.
9
Department of Anesthesiology, University of Colorado School of Medicine, Aurora, CO, USA.

Abstract

Background and Aims:

Cannabinoid receptor stimulation may have positive symptomatic effects on inflammatory bowel disease [IBD] patients through analgesic and anti-inflammatory effects. The cannabinoid 2 receptor [CB2R] is expressed primarily on immune cells, including CD4+ T cells, and is induced by active inflammation in both humans and mice. We therefore investigated the effect of targeting CB2R in a preclinical IBD model.

Methods:

Employing a chronic ileitis model [TNFΔARE/+ mice], we assessed expression of the CB2R receptor in ileal tissue and on CD4+ T cells and evaluated the effect of stimulation with CB2R-selective ligand GP-1a both in vitro and in vivo. Additionally, we compared cannabinoid receptor expression in the ilea and colons of healthy human controls with that of Crohn's disease patients.

Results:

Ileal expression of CB2R and the endocannabinoid anandamide [AEA] was increased in actively inflamed TNF∆ARE/+ mice compared with controls. CB2R mRNA was preferentially induced on regulatory T cells [Tregs] compared with T effector cells, approximately 2.4-fold in wild-type [WT] and 11-fold in TNF∆ARE/+ mice. Furthermore, GP-1a enhanced Treg suppressive function with a concomitant increase in IL-10 secretion. GP-1a attenuated murine ileitis, as demonstrated by improved histological scoring and decreased inflammatory cytokine expression. Lastly, CB2R is downregulated in both chronically inflamed TNF∆ARE/+ mice and in IBD patients.

Conclusions:

In summary, the endocannabinoid system is induced in murine ileitis but is downregulated in chronic murine and human intestinal inflammation, and CB2R activation attenuates murine ileitis, establishing an anti-inflammatory role of the endocannabinoid system.

KEYWORDS:

Inflammatory bowel disease; endocannabinoid; regulatory T cell

PMID:
28981653
PMCID:
PMC5881726
DOI:
10.1093/ecco-jcc/jjx096
[Indexed for MEDLINE]
Free PMC Article

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