Introduction Ulcerative colitis (UC) is an inflammatory disease of the colonic mucosa driven by a Th2-like response in which IL-13 leads to toxic effects to the mucosa and activation of the IL-13/STAT6 pathways. Inhibition of STAT6 activation has been shown to reduce the inflammatory response in UC. MicroRNAs are small non-coding RNAs inhibiting gene expression by pairing to the 3’ UnTranslated Region (3’UTR) of their target mRNAs facilitating their translational repression/degradation. MiR-31 and miR-155 have been shown to be up-regulated in active UC and are involved in the regulation of innate and adaptive immune responses. Both microRNAs have been identified to target IL13Rα1.
Methods Paired biopsies from inflamed and non-inflamed areas of the sigmoid colon were taken in 11 UC patients. MicroRNA expression and mRNA expression of IL-13 dependant genes were assessed by qPCR. In vitro experiments on a human colonic cell line (HT-29 cells) and a macrophage/monocytic cell line (THP-1 cells) were stimulated with IL-13. SOCS1 and IL13Rα1 mRNA expression were measured by qPCR in the presence or absence of transfection with pre-miR-31, pre-miR-155 or a combination of both. Data were analysed using the Wilcoxon matched pairs test.
Results Our data shows a significant up-regulation of miR-31 and miR-155, as well as significant increase of IL-13 dependant mRNA expression of CCL18, SOCS1, Serpine and MMP-9 and a decrease of IL13Rα1 mRNA expression by 30% in the active segments of UC as compared to inactive disease. In vitro experiments on HT-29 cells and on THP-1 cells showed a marked reduction of mRNA expression of SOCS1 and IL13Rα1 in both cell types after treatment with pre-miR-31 and pre-miR-155 and their combination at a quarter of the original dose of each single pre-miR was equally efficacious.
Conclusion Our data reveals a clear up-regulation of miR-31 and miR-155 in inflamed UC as compared to neighbouring inactive tissue in the same patient. IL-13 dependant mRNA expression is also significantly increased in the same samples. The fact that IL13Rα1 mRNA expression is down-regulated in active disease in the presence of high levels of miR-31 and miR-155 may indicate a protective role for these microRNAs attempting to reduce IL13Rα1 expression and therefore the STAT6 pathway activation by IL-13 through IL13Rα1. Reduction of IL13Rα1 mRNA expression in our in vitro models transfected with pre-miRs confirms this finding. Interestingly the combination of the two microRNAs at lower doses achieving the same effect may indicate a possible synergy of action. MicroRNAs targeting IL13Rα1 in UC could have a potential therapeutic effect by down-regulation of the IL-13/STAT6 pathway and combination of microRNAs may have a synergistic effect.
Competing interests None declared.
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