Can a microRNA Control Inflammation in Patients With Ulcerative Colitis?

Loss of a non-coding RNA that regulates inflammation could contribute to development of ulcerative colitis (UC) in children, according to the October issue of Gastroenterology.

UC and Crohn’s disease are chronic inflammatory bowel diseases that affect adults and children. These diseases are complex, and caused by combinations of genetic and environmental factors that disrupt the mucosal immune system.

Of the more than 1 million individuals with inflammatory bowel diseases in the United States, approximately 100,000 are children. Much can be learned by studying the genetic factors that contribute to inflammatory bowel diseases in children, because they have been exposed to fewer environmental factors than adults.

One of the immune regulatory processes that is altered in patients with UC involves signaling by interleukin 6 (IL6) through its receptor and STAT3. STAT3 becomes activated via phosphorylation to regulate expression of genes that encode many cytokines and growth factors. The IL6–STAT3 pathway is upregulated in adult patients with UC, and promotes progression of UC to colon cancer. But how does this pathway become active in these patients?

Georgios Koukos et al. found that levels of the microRNA (MIR)124 were decreased, whereas activation of STAT3 (based on its phosphorylation) was increased, in colon tissues from pediatric patients with active UC, compared with those with inactive disease. Koukos et al. also found levels of MIR124 and STAT3 to be inversely correlated in colon tissues from mice with colitis.

MIRs are small, noncoding RNAs that bind complementary sequences within mRNA molecules to prevent their translation or induce their degradation. The human genome is believed to encode more than 1000 MIRs, which regulate expression of about 60% of mammalian genes. Koukos et al. showed that MIR124 interacted directly with STAT3 mRNA.

So, lower levels of MIR124 in colon tissues of patients would result in increased levels of STAT3, resulting in activation of the inflammatory response.

But how is miR124 reduced in colon tissues of patients? Koukos et al. found the promoter region of the gene that encodes MIR124 to be hypermethylated in tissues from children with UC (see below figure).

In colon tissues from pediatric patients with UC, methylation in the promoter region of MIr124 reduces its expression. Reduced levels of MIR124 lead to increased levels of STAT3 and increased activation of its target genes, which include VEGF, BCL2, BCLXL, and MMP9

In colon tissues of patients without UC (non-IBD), expression of MIR124 reduces levels of STAT3 and thereby prevents activation of its target genes. In colon tissues from pediatric patients with UC, methylation in the promoter region of MIR124 reduces its expression. Reduced levels of MIR124 lead to increased levels of STAT3 and activation of its target genes, which include VEGF, BCL2, BCLXL, and MMP9.

In support of this model, incubation of colonocytes with 5-AZA, which demethylates DNA, upregulated miR124 and reduced levels of STAT3 mRNA.

These findings fit with other reports of alterations in DNA methylation in patients with inflammatory bowel diseases, although the affected genes vary.

Koukos et al. explain that identifying factors that are uniquely de-regulated in pediatric patients with UC, compared with adults, is valuable for distinguishing the different stages of this disease.

MIR124 might be a biomarker, even a therapeutic target, for active UC in pediatric patients. Strategies to alter the epigenetically regulated MIR124–STAT3 pathway might also lead to new treatments for inflammatory bowel diseases and cancer.

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About Kristine Novak, PhD, Science Editor

Dr. Kristine Novak is the science editor for Gastroenterology and Clinical Gastroenterology and Hepatology, both published by the American Gastroenterological Association. She has worked as an editor at biomedical research journals and as a science writer for more than 12 years, covering advances in gastroenterology, hepatology, cancer, immunology, biotechnology, molecular genetics, and clinical trials. She has a PhD in cell biology and an interest in all areas of medical research.
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