MicroRNA-31 and MicroRNA-155 Are Overexpressed in Ulcerative Colitis and Regulate IL-13 Signaling by Targeting Interleukin 13 Receptor α-1.

Markus Gwiggner,Andy Claridge,Rocio Martinez-Nunez,Tilman Sanchez-Elsner,Simon Whiteoak,Victor Bondanese,Jane Collins,J Cummings

doi:10.3390/genes9020085

Abstract

Interleukin-13 (IL-13) is an important Type 2 T helper (Th2) cytokine, controlling biological functions in epithelium and has been linked to asthma, atopic dermatitis and ulcerative colitis (UC). Interleukin-13 signals through IL-13 receptor α-1 (IL13RA1 (gene) and IL13Rα1 (protein)), a receptor that can be regulated by microRNAs (miRs). MicroRNAs are small non-coding single-stranded RNAs with a role in several pathologies. However, their relevance in the pathophysiology of UC, a chronic inflammatory condition of the colonic mucosa, is poorly characterised. Here, we determined the expression of IL13Rα1 in UC, its potential regulation by miRs and the subsequent effect on IL-13 signalling. Inflamed mucosa of UC patients showed decreased mRNA and protein expression of IL13RA1 when compared to healthy controls. We show that miR-31 and miR-155 are upregulated in inflamed UC mucosa and that both directly target the 3′ untranslated region of IL13RA1 mRNA. Transfection of miR-31 and miR-155 mimics reduced the expression of IL13RA1 mRNA and protein, and blocked IL-13-dependent phosphorylation of signal transducer and activator of transcription 6 (STAT6) in HT-29 cells, a gut epithelium cell line. Interleukin-13 activation of suppressor of cytokine signaling 1 (SOCS1) and eotaxin-3 (CCL26) expression was also diminished. MicroRNA-31/microRNA-155 mimics also downregulated IL13RA1 in ex vivo human inflamed UC biopsies. We propose that miR-31 and miR-155 have an important role in limiting IL-13 signalling in UC disease.

Highlights

Interleukin-13 is a Type 2 T helper (Th2) cytokine that is believed to be required for normal immune function, such as defence against gastrointestinal nematodes and intracellular infections [1].It has been suggested to have a role in mucosal inflammation and fibrosis in chronic diseases, including asthma, atopic dermatitis, eosinophilic oesophagitis and ulcerative colitis (UC) [1,2].Genes 2018, 9, 85; doi:10.3390/genes9020085 www.mdpi.com/journal/genesUlcerative colitis and Crohn’s disease represent the two main types of inflammatory bowel disease [3]
Given that IL-13 signalling depends on the binding to the IL13Rα1 subunit [13], we first investigated the expression of IL13RA1 in UC
Our work demonstrates a role for miR-31 and miR-155 in the regulation of IL-13 signalling

Summary

Introduction

Interleukin-13 is a Type 2 T helper (Th2) cytokine that is believed to be required for normal immune function, such as defence against gastrointestinal nematodes and intracellular infections [1]. Ulcerative colitis and Crohn’s disease represent the two main types of inflammatory bowel disease [3]. Ulcerative colitis is a relapsing, idiopathic, chronic inflammatory condition of the colonic mucosa in genetically predisposed individuals [4,5] who are believed to mount an inappropriate immune response to their gut microflora or other environmental agents [6]. Interleukin-13 producing cells, including natural killer T cells (NKT) and macrophages, can be found in the healthy and non-inflamed human lamina propria [7,8]. Studies in UC have reported increased release of IL-13 from activated lamina propria mononuclear cells [9]

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