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Br J Pharmacol. 2017 Aug;174(15):2501-2511. doi: 10.1111/bph.13860. Epub 2017 Jun 21.

Stimulation of autophagy prevents intestinal mucosal inflammation and ameliorates murine colitis.

Author information

1
FISABIO, Hospital Dr. Peset, Valencia, Spain.
2
Departamento de Farmacología and CIBERehd, Facultad de Medicina, Universidad de Valencia, Valencia, Spain.
3
Departamento de Medicina, Facultad de Medicina, Universidad de Valencia, Valencia, Spain.

Abstract

BACKGROUND AND PURPOSE:

Defective autophagy contributes to the pathogenesis of inflammatory disorders such as inflammatory bowel disease and there are interactions between autophagy and inflammation. Here we have analysed the effects of autophagy stimulators on murine colitis.

EXPERIMENTAL APPROACH:

Mice were treated with intrarectal administration of 2,4,6-trinitrobenzenesulfonic acid (TNBS) (3.5 mg·20 g-1 ) and body weight was measured daily. Histological damage was scored 2 or 4 days after treatment. Some mice received trehalose (3% in drinking water 3 weeks before TNBS administration) or a daily administration of rapamycin (1.25 mg·kg-1 , i.p.), betanin (1 g·kg-1 , i.p.) or betanin + 3-methyladenine (3MA) (10 mg·kg-1 , i.p.). Protein levels of p-mTOR, p62, LC3, BCL10, NFκB, IκBα and p-IκBα in mucosa were determined by Western blots and mRNA expression of TNFα, IL1β, IL6, IL10, COX2, CCR7, CD11c, inducible NOS and CD86 by qRT-PCR.

KEY RESULTS:

Impaired autophagy associated with body weight loss and intestinal damage was detected in the mucosa of TNBS-treated mice. Administration of trehalose, rapamycin or betanin prevented the impaired autophagic flux induced by TNBS and decreased mucosal protein levels of BCL10, p-IκBα and NFκB-p65 and the expression of pro-inflammatory cytokines and M1 macrophage markers. Blockade of autophagosome formation by treatment with 3MA, prevented the reduction in protein levels of p62, BCL10, p-IκBα and NFκB-p65 induced by betanin in TNBS-treated mice and weakened the protective effects of betanin on murine colitis.

CONCLUSIONS AND IMPLICATIONS:

Pharmacological stimulation of mucosal autophagy reduced intestinal inflammation and improved murine colitis.

PMID:
28500644
PMCID:
PMC5513861
DOI:
10.1111/bph.13860
[Indexed for MEDLINE]
Free PMC Article

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