miR-301a promotes intestinal mucosal inflammation through induction of IL-17A and TNF-α in IBD.

Abstract

OBJECTIVE:

MicroRNA (miR)-301a is known to be involved in the tumourigenesis and pathogenesis of several autoimmune diseases, but it remains unclear whether miR-301a is associated with the pathogenesis of IBD.

METHODS:

miR-301a expression was assessed in peripheral blood mononuclear cells (PBMC) and inflamed mucosa of patients with IBD by quantitative real-time-PCR. Peripheral blood CD4+ T cells were transduced with lentivirus-encoding pre-miR-301a (LV-miR-301a) or a reverse complementary sequence of miR-301a (LV-anti-miR-301a), and their differentiation and activation were investigated in vitro. Antisense miR-301a was administered into mice during trinitrobenzene sulphonic acid (TNBS)-induced colitis to determine its role in colitis.

RESULTS:

miR-301a expression was significantly upregulated in PBMC and inflamed mucosa of patients with IBD compared with healthy controls. Stimulation with tumour necrosis factor-α (TNF-α) significantly enhanced miR-301a expression in IBD CD4+ T cells, which was markedly reversed by anti-TNF-α mAb (Infliximab) treatment. Transduction of LV-miR-301a into CD4+ T cells from patients with IBD promoted the Th17 cell differentiation and TNF-α production compared with the cells with expression of LV-anti-miR-301a. SNIP1 as a functional target of miR-301a was reduced in miR-301a expression but increased in LV-anti-miR-301a expression. Knockdown of SNIP1 could enhance Th17 cell differentiation. Furthermore, intracolonical administration of antisense miR-301a in TNBS-induced mouse colitis model significantly decreased numbers of interleukin (IL)-17A+ cells and amounts of pro-inflammatory cytokines (eg, IL-17A, TNF-α) in inflamed colon.

CONCLUSIONS:

Our data reveal a novel mechanism in which the elevated miR-301a in PBMC and inflamed mucosa of IBD promotes Th17 cell differentiation through downregulation of SNIP1. Blockade of miR-301a in vivo may serve as a novel therapeutic approach in the treatment of IBD.

• Authors: Chong He, Yan Shi, Ruijin Wu, Mingming Sun, Leilei Fang, Wei Wu, Changqin Liu, Maochun Tang, Zhong Li, Ping Wang, Yingzi Cong, Zhanju Liu
• Journal: Gut (Gut) Vol. 65 Issue 12 Pg. 1938-1950 (12 2016) ISSN: 1468-3288 [Electronic] England
• PMID: 26338824 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/.

Chemical References

• Biomarkers
• Interleukin-17
• MIRN301A microRNA, human
• MicroRNAs
• Tumor Necrosis Factor-alpha

Topics

• Animals
• Biomarkers (blood)
• CD4-Positive T-Lymphocytes (immunology)
• Case-Control Studies
• Disease Models, Animal
• Humans
• In Vitro Techniques
• Inflammation (immunology)
• Inflammatory Bowel Diseases (blood, drug therapy, immunology, pathology)
• Interleukin-17 (blood, immunology)
• Intestinal Mucosa (immunology, pathology)
• Mice
• MicroRNAs (blood, immunology)
• Prognosis
• Severity of Illness Index
• Tumor Necrosis Factor-alpha (antagonists & inhibitors, immunology)