Temporal Colonic Gene Expression Profiling in the Recurrent Colitis Model Identifies Early and Chronic Inflammatory Processes

Bas Kremer,Tonny Lagerweij,Lex Nagelkerken,Rob Mariman,Marjan van Erk,Benoit Foligne

doi:10.1371/journal.pone.0050388

Abstract

The recurrent TNBS-colitis model in BALB/c mice has been proposed as a model of Inflammatory Bowel Disease with a shifting pattern of local cytokines with the expression of Th1 cytokines during the early phase, Th17 cytokines during the intermediate phase and Th2 cytokines during late fibrotic stages. In this study, we evaluated the development of pathology in time–in conjunction with genome-wide gene expression in the colons–in response to three weekly intrarectal instillations of TNBS. During this time-frame mice develop colitis with extensive cellular infiltration of (sub)mucosa and mildly to moderately affected crypt architecture. These pathological processes were sensitive to local treatment with budesonide. Gene expression profiling confirmed an acute phase response after each intrarectal TNBS-challenge. In addition, a chronic inflammatory process developed over time particularly evident from a gradual increase in expression of mast cell related genes. The changes in pathological hallmarks were consistent with a temporal expression of mRNA encoding a selection of chemokines. In conclusion, the early stages of the recurrent TNBS-colitis model reflect several aspects of inflammatory bowel disease which are sensitive to immunomodulation.

Highlights

Inflammatory Bowel Diseases (IBD), with Ulcerative Colitis (UC) and Crohn’s Disease (CD) as major entities, are chronic inflammatory disorders of the gastrointestinal tract, affecting an estimated 3.6 million people in Europe and the US [1]
Most IBD models result from exogenous manipulation; they can be categorized based on induction by chemicals, immune cell transfer, or gene targeting [19]
Models based on immune cell transfer, such as the CD45RBHi T-cell transfer model, and models based on gene targeting, such as the IL-10 knockout mouse model, present excellent models to study mechanisms involved in the pathogenesis IBD [20]

Summary

Introduction

Inflammatory Bowel Diseases (IBD), with Ulcerative Colitis (UC) and Crohn’s Disease (CD) as major entities, are chronic inflammatory disorders of the gastrointestinal tract, affecting an estimated 3.6 million people in Europe and the US [1]. IBD may be chronic or relapsing in nature, possibly due to a process of inflammation following an exaggerated immune response against enteric microorganisms. These processes affect intestinal function leading to diarrhea, cramping, and abdominal pain. Acute colitis models such as dextrane sodium sulphate (DSS) and the 2,4,6-trinitrobenzene sulfonic acid (TNBS) induced colitis are used [4,5]. These models are characterized by severe acute inflammation of the colon representing histopathological aspects that reflect human IBD. Efficacies of a limited number of relevant treatments have been reported in these models [7,8,9]

Methods

Results

Conclusion