Open AccessCannabinoid receptor 2 agonist promotes parameters implicated in mucosal healing in patients with inflammatory bowel disease
Author(s) -
Tartakover Matalon Shelly,
Ringel Yehuda,
Konikoff Fred,
Drucker Liat,
Pery Shaul,
Naftali Timna
Publication year - 2020
Publication title -
ueg journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.667
H-Index - 35
eISSN - 2050-6414
pISSN - 2050-6406
DOI - 10.1177/2050640619889773
Subject(s) - mmp9 , cannabinoid receptor , cannabinoid receptor agonists , inflammation , medicine , cannabinoid , apoptosis , agonist , inflammatory bowel disease , cannabinoid receptor type 2 , cancer research , receptor , immunology , pharmacology , biology , downregulation and upregulation , biochemistry , disease , gene
Background Cannabis benefits patients with inflammatory bowel disease (IBD). Cannabinoid receptors are expressed in gut immune cells and in epithelial cells of inflamed guts. Mucosal healing (MH) requires epithelial layer restoration. Objective To analyze the effects of CB2 agonist on parameters implicated in gut inflammation and MH. Methods Mucosal samples from areas of inflamed/uninflamed colon from 16 patients with IBD were cultured without/with cannabinoid receptor 2 (CB2) agonist (JWH‐133, 10 µM, 6 hours (hr)), and analyzed for epithelial/stromal cell proliferation, apoptosis (secretome matrix metalloproteinase 9 (MMP9) activity, which impairs epithelial permeability) and interleukin‐8 (IL‐8) levels ( n = 5–9). In addition, Caco‐2 (colon carcinoma epithelial cells) were cultured with biopsy secretomes (48 hr), and analyzed for phenotype and protein markers of proliferation (proliferating cell nuclear antigen), autophagy (LC3IIB) and permeability (Zonula occludens‐1) ( n = 4–6). Results Uninflamed tissue had higher epithelial proliferation (Ki67: 50%↑, p < 0.05), and reduced secretome MMP9 activity and IL‐8 levels (>50%↓, p < 0.05) compared to inflamed tissue. Treatment with CB2 agonist had no effect on epithelial apoptosis, but increased epithelial Ki67 expression (25%), and reduced secretome MMP9 and IL‐8 levels in inflamed biopsies. Secretomes of CB2‐treated biopsies increased Caco‐2 number, migration, proliferating cell nuclear antigen and LC3IIB expression (all, p < 0.05), but had no effect on ZO‐1. Conclusion Using ex vivo and in vitro human models, we demonstrated that manipulating the cannabinoid system affects colon cells and secretome characteristics that facilitate MH in IBD.