Inhibition of Epithelial TNF-α Receptors by Purified Fruit Bromelain Ameliorates Intestinal Inflammation and Barrier Dysfunction in Colitis.

Jianyi Dong,Jingyu Wang,Dapeng Chen,Jinyong Peng,Chen Wang,Lianhong Yin,Liang Wang,Yongjian Xiong,Panpan Feng,Yuan Lin,Shengxu Zhi,Zijuan Zhou

doi:10.3389/fimmu.2017.01468

Abstract

Activation of the TNF-α receptor (TNFR) leads to an inflammatory response, and anti-TNF therapy has been administered to reduce inflammation symptoms and heal mucosal ulcers in inflammatory bowel disease (IBD). Bromelain, a complex natural mixture of proteolytic enzymes, has been shown to exert anti-inflammatory effects. This study aimed to investigate the effect of purified fruit bromelain (PFB)-induced inhibition of epithelial TNFR in a rat colitis model. Colitis was established by intracolonic administration of 2, 4, 6-trinitrobenzene sulfonic acid. Expression of TNFR1 and TNFR2 was measured by quantitative RT-PCR and western blotting. The effect of PFB on colitis was evaluated by examining the inflammatory response and intestinal epithelial barrier function. Our results showed that both TNFR1 and TNFR2 expression were significantly increased in a colitis model, and the increase was significantly reversed by PFB. Colitis symptoms, including infiltration of inflammatory cells, cytokine profiles, epithelial cell apoptosis, and epithelial tight junction barrier dysfunction were significantly ameliorated by PFB. Compared with fruit bromelain and stem bromelain complex, the inhibition of TNFR2 induced by PFB was stronger than that exhibited on TNFR1. These results indicate that PFB showed a stronger selective inhibitory effect on TNFR2 than TNFR1. In other words, purification of fruit bromelain increases its selectivity on TNFR2 inhibition. High expression of epithelial TNFRs in colitis was significantly counteracted by PFB, and PFB-induced TNFR inhibition ameliorated colitis symptoms. These results supply novel insights into potential IBD treatment by PFB.

Highlights

Inflammatory bowel diseases (IBDs) are a group of recurrent inflammatory conditions of the colon and small intestine mainly of ulcerative colitis and Crohn’s disease [1]
The expression level of TNF-α receptor (TNFR) including TNFR1 and TNFR2 were significantly increased in a rat colitis model, and purified fruit bromelain (PFB)-induced reduction of TNFR1 and TNFR2 ameliorated colitis symptoms
Both expression changes of TNFR1 and TNFR2 are involved in the inflammatory response in IBD; TNFR2 but not TNFR1 is involved in regulation of tight junction barrier function [25]

Summary

Introduction

Inflammatory bowel diseases (IBDs) are a group of recurrent inflammatory conditions of the colon and small intestine mainly of ulcerative colitis and Crohn’s disease [1]. TNF-α leads to the activation of nuclear factor kappa B (NF-κB), which can transmigrate into the nucleus, and it binds to DNA response elements in gene promoter regions to control transcription of genes, such as inducible NO synthase (iNOS), cyclo-oxygenase-2 (COX2), and myosin light chain kinase (MLCK) [3, 4]. Both iNOS and COX2 are proinflammatory mediators which play crucial roles in inflammatory responses [3]. Epithelial TNFR1 and TNFR2 are relatively under-examined, but they have been implicated in epithelial apoptosis, proliferation, migration, and tight junction regulation [7,8,9]

Objectives

Methods

Results

Conclusion