miR-19b downregulates intestinal SOCS3 to reduce intestinal inflammation in Crohn's disease.

Abstract

Although aberrant microRNA (miRNA) expression has frequently been observed in inflammatory bowel disease (IBD), its biological functions and targets remain largely unknown. Present study found that miR-19b was significantly downregulated in active Crohn's disease (CD). Using bioinformatics analysis, suppressor of cytokine signalling 3 (SOCS3), a physiological regulator of innate and adaptive immunity that controls several immuno-inflammatory diseases, was predicted to be a potential target of miR-19b. An inverse correlation between miR-19b and SOCS3 protein levels, but not mRNA, was identified in active-CD intestinal tissue samples. By overexpressing or knocking down miR-19b in Caco2 cells and HT29 cells, it was experimentally validated that miR-19b is a direct regulator of SOCS3. Using a luciferase reporter assay, it was confirmed that miR-19b directly recognizes the 3'-untranslated region (3'-UTR) of SOCS3. Furthermore, overexpression of miR-19b decreased SOCS3 expression, leading to increased production of macrophage-inflammatory protein-3α (MIP-3α) in Caco2 cells. In contrast, knockdown of miR-19b increased SOCS3 and decreased MIP-3α. Finally, intracolonically delivered miR-19b decreased the severity of colitis induced with 2,4,6-trinitrobenzene sulphonic acid (TNBS). Taken together, our findings suggest that miR-19b suppresses the inflammatory response by inhibiting SOCS3 to modulate chemokine production in intestinal epithelial cells (IECs) and thereby prevents the pathogenesis of CD.

• Authors: Xiuqin Cheng, Xiaofei Zhang, Jiewen Su, Yingdi Zhang, Weimei Zhou, Jun Zhou, Cheng Wang, Hongwei Liang, Xi Chen, Ruihua Shi, Ke Zen, Chen-Yu Zhang, Hongjie Zhang
• Journal: Scientific reports (Sci Rep) Vol. 5 Pg. 10397 (May 22 2015) ISSN: 2045-2322 [Electronic] England
• PMID: 25997679 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• 3' Untranslated Regions
• CCL20 protein, human
• Chemokine CCL20
• Chemokines
• MIRN19 microRNA, human
• MicroRNAs
• RNA, Messenger
• RNA, Small Interfering
• RNA, Untranslated
• SOCS3 protein, human
• Suppressor of Cytokine Signaling 3 Protein
• Suppressor of Cytokine Signaling Proteins
• Trinitrobenzenesulfonic Acid

Topics

• 3' Untranslated Regions
• Adult
• Animals
• Base Sequence
• Caco-2 Cells
• Chemokine CCL20 (metabolism)
• Chemokines (metabolism)
• Colitis (chemically induced, pathology, prevention & control)
• Crohn Disease (genetics, pathology)
• Down-Regulation (drug effects)
• Female
• HT29 Cells
• Humans
• Immunohistochemistry
• In Situ Hybridization, Fluorescence
• Intestinal Mucosa (metabolism)
• Male
• Mice
• MicroRNAs (antagonists & inhibitors, genetics, metabolism)
• Middle Aged
• RNA Interference
• RNA, Messenger (metabolism)
• RNA, Small Interfering (metabolism)
• RNA, Untranslated (metabolism)
• Rats
• Real-Time Polymerase Chain Reaction
• Sequence Alignment
• Suppressor of Cytokine Signaling 3 Protein
• Suppressor of Cytokine Signaling Proteins (antagonists & inhibitors, genetics, metabolism)
• Trinitrobenzenesulfonic Acid (toxicity)