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 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.