Gastroenterology

Gastroenterology

Volume 135, Issue 5, November 2008, Pages 1624-1635.e24
Gastroenterology

Basic—Alimentary Tract
MicroRNAs Are Differentially Expressed in Ulcerative Colitis and Alter Expression of Macrophage Inflammatory Peptide-2α

https://doi.org/10.1053/j.gastro.2008.07.068Get rights and content

Background & Aims

Chronic inflammatory bowel diseases such as ulcerative colitis (UC) are associated with differential expression of genes involved in inflammation and tissue remodeling. MicroRNAs (miRNAs), which direct mRNA degradation and translational inhibition, influence a number of disease processes. We examined whether miRNAs are differentially expressed in UC tissues and are associated with expression of genes that regulate inflammation.

Methods

miRNA expression was assessed in patients with active UC, inactive UC, Crohn's disease, irritable bowel syndrome, infectious colitis, and microscopic colitis, as well as in healthy subjects by microarray, quantitative reverse transcription-polymerase chain reaction and in situ hybridization analyses. Colonic epithelial cell (HT29) expression of miRNAs was assessed. Regulation of gene expression by miRNAs was assessed by luciferase reporter construct assays and transfection of specific miRNA mimics.

Results

Active UC was associated with the differential expression of 11 miRNAs; 3 were significantly decreased and 8 were significantly increased in UC tissues. In situ hybridization analysis indicated that miR-192, an miRNA with decreased expression in active UC, was predominantly localized to colonic epithelial cells. Macrophage inflammatory peptide (MIP)-2α, a chemokine expressed by epithelial cells, was identified as a target of miR-192. In colon epithelial cells, induction of MIP-2α expression by tumor necrosis factor-α was accompanied by a concomitant reduction in miR-192 expression and miR-192 was observed to regulate the expression of MIP-2α.

Conclusions

These findings expand the known roles of miRNAs, indicating that tissues from patients with UC, and possibly other chronic inflammatory diseases, have altered miRNA expression patterns. These findings also demonstrate that miRNAs regulate colonic epithelial cell-derived chemokine expression.

Section snippets

Human Tissues

Colonoscopic pinch biopsies from the sigmoid colon of patients with chronic active UC, chronic inactive UC, chronic active colonic CD, IBS, IC, MC, and normal, healthy patients undergoing screening colonoscopies (Table 1) were obtained using a protocol approved by The Johns Hopkins University Institutional Review Board. In total, 62 patient biopsies were assessed. The diagnoses of active UC, inactive UC, MC (2 cases of collagenous colitis and 1 case of lymphocytic colitis), and CD were

miRNAs Are Differentially Expressed in UC Tissues

We first sought to determine whether miRNAs are differentially expressed in active UC.

Sigmoid colon pinch biopsies from patients with histologically confirmed active UC, inactive UC, and normal, healthy control subjects were obtained. Additional control groups used for comparison included patients with IBS, IC, MC, and CD. Clinical characteristics of each patient group are listed in Table 1.

An miRNA microarray capable of measuring the expression of 553 known human miRNA genes was used to

Discussion

In this study, we demonstrated that miRNAs are differentially expressed in the tissues of patients with active UC as compared with normal, healthy control subjects. Specifically, we identified 8 up-regulated and 3 down-regulated miRNAs in active UC tissues. The pattern of expression of these active UC-associated miRNAs was distinct from other conditions, including inactive UC, IC, MC, CD, and IBS. This study is the first to link chronic IBD with altered expression of miRNAs, thereby expanding

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    NCBI Gene Expression Omnibus (http://www.ncbi.nlm.nih.gov/geo), accession # GSE10791.

    Supported by National Institutes of Health grants K08DK078046 (to J.H.K.) and R24DK064388 and by Broad Medical Research Program grants IBD-0051 (to F.W. and S.C.) and IBD-0212 (F.W. and J.H.K.). J.H.K. was also supported by the Sherlock Hibbs IBD Research Fund, the M. Alan Guerrieri Family Fund and the Meyerhoff IBD Center at The Johns Hopkins University.

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