Role of DDX3 in the pathogenesis of inflammatory bowel disease.

Saritha Tantravedi,Paul T Winnard,Farhad Vesuna,Venu Raman,Paul J Van Diest,Marise R Heerma Van Voss

doi:10.18632/oncotarget.23323

Saritha Tantravedi, Paul T Winnard + Show 4 more

Open Access

https://doi.org/10.18632/oncotarget.23323

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Abstract

When crypt stem cells of the gastrointestinal tract become injured, the result is increased synthesis of pro-inflammatory cytokines and matrix metalloproteinases by their progeny – the colonic epithelium. Chronic inflammation of the gastrointestinal tract is a characteristic of inflammatory bowel disease, which includes Crohn’s Disease and Ulcerative Colitis. In our ongoing investigation to decipher the characteristic functions of a RNA helicase gene, DDX3, we identified high DDX3 expression by immunohistochemistry of colon biopsy samples, which included chronic/mild Morbus Crohn, active Morbus Crohn, Chronic/mild Colitis Ulcerosa and active Colitis Ulcerosa in epithelium and stromal compartments. We used a small molecule inhibitor of DDX3, RK-33, on two human colonic epithelial cell lines, HCEC1CT and HCEC2CT and found that RK-33 was able to decrease expression of MMP-1, MMP-2, MMP-3, and MMP-10. Moreover, forced differentiation of a human colonic cancer cell line, HT29, resulted in decreased DDX3 levels, indicating that DDX3 contributes to the modulation of colonic epithelium differentiation. In conclusion, our results revealed novel functions of DDX3 in inflammatory bowel disease and indicate a potential for using RK-33 as a systemic therapy to promote not only differentiation of transformed colonic epithelium but also to reduce MMP expression and thus elicit a decreased inflammatory response.

Highlights

The colonic epithelium provides a necessary barrier to protect the internal milieu of the intestine from the potentially injurious luminal environment [1, 2]
Crypt stem cells are susceptible to injury that can lead to increased synthesis of inflammatory cytokines and matrix metalloproteinases by their progeny, the colonic epithelium [3,4,5,6]
Given that DDX3 expression is high during active inflammation (Figure 1), these results indicate that targeting DDX3 with RK-33 can reduce the expression levels of several key matrix metalloproteinases (MMPs) involved in inflammation and, as such, provides an indication that targeting DDX3 in inflammatory bowel diseases (IBD) patients may be effective at controlling MMP- mediated inflammation

Summary

Introduction

The colonic epithelium provides a necessary barrier to protect the internal milieu of the intestine from the potentially injurious luminal environment [1, 2]. Even after long-term treatment with severe immunosuppressive agents, many of these patients eventually require colectomies and IBD remains associated with an increase in intermediate and long-term mortality of 10% and 50% for UC and CD, respectively [14] This has spurred further research and insights into the complex interactions between the immune system, abdominal microflora, and the intestinal epithelium all of www.impactjournals.com/oncotarget which contribute to the pathogenesis of IBD. Such studies have provided evidence that enterocytes (columnar epithelial cells) trigger and enhance a local immune response by the production of proinflammatory cytokines and matrix metalloproteinases (MMPs) [15, 16]

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