Resveratrol Downregulates miR‐31 to Promote T Regulatory Cells during Prevention of TNBS‐Induced Colitis

• Published in: Molecular nutrition & food research 2020-01, Vol.64 (1), p.e1900633-n/a
• Main Authors: Alrafas, Haider Rasheed, Busbee, Philip B., Nagarkatti, Mitzi, Nagarkatti, Prakash S.
• Format: Article
• Language: English
• Subjects: Animals; Attenuation; Case-Control Studies; CD4 antigen; colitis; Colitis - chemically induced; Colitis - drug therapy; Colitis - genetics; Colitis - prevention & control; Colitis, Ulcerative - genetics; Colon; Cytokines; DNA microarrays; Down-Regulation - drug effects; Female; Forkhead Transcription Factors - genetics; Forkhead Transcription Factors - metabolism; Foxp3 protein; Gene Expression Regulation - drug effects; Helper cells; Humans; Immune system; Immunoregulation; Inflammatory bowel disease; Inflammatory bowel diseases; Intestine; Lymphocytes; Lymphocytes T; Mice, Inbred C57BL; microRNA; MicroRNAs - genetics; miRNA; miR‐31; Mucosal immunity; Polymerase chain reaction; regulatory T cells; Resveratrol; Resveratrol - pharmacology; Ribonucleic acid; RNA; T-Lymphocytes, Regulatory - drug effects; T-Lymphocytes, Regulatory - physiology; Th17 Cells - drug effects; Therapeutic applications; Transcription factors; Transfection; Trinitrobenzenesulfonic Acid - toxicity; Ulcerative colitis
• ISSN: 1613-4125; 1613-4133
• DOI: 10.1002/mnfr.201900633

Scope Colitis, an inflammatory bowel disease, is associated with aberrant regulation of the colonic mucosal immune system. Resveratrol, a natural plant product, has been found to exert anti‐inflammatory properties and attenuate the development of murine colitis. In the current study, the role of microRNA (miR) in the ability of resveratrol to suppress colonic inflammation is examined. Methods and results BALB/C mice with 2,4,6‐Trinitrobenzenesulfonic acid solution (TNBS)‐induced colitis, when treated with resveratrol, show improved clinical outcomes and reduce induction of inflammatory T cells (Th17 and Th1) while increasing CD4+Foxp3+ regulatory T cells (Tregs) and IL‐10‐producing CD4+ T cells. miR microarray analysis and polymerase chain reaction (PCR) validation from CD4+ T cells show treatment with resveratrol decreases the expression of several miRs (miR‐31, Let7a, miR‐132) that targets cytokines and transcription factors involved in anti‐inflammatory T cell responses (Foxp3 and TGF‐β). Transfection studies with miR‐31 confirm that this miR directly regulates the expression of Foxp3. Lastly, analysis of public data from human patients with ulcerative colitis reveals that miR‐31 expression is significantly increased when compared to controls. Conclusion Together, the current study demonstrates that resveratrol‐mediated attenuation of colitis may be regulated by miR‐31 through induction of Tregs and miR‐31 may serve as a therapeutic target for human colitis. Colitis leads to dysregulation of microRNA (miR), which is characterized by an increase in microRNA‐31 (miR‐31). During colitis, miR‐31 promotes a pro‐inflammatory T helper 17 (Th17) phenotype by targeting anti‐inflammatory regulatory T cell (Treg) transcription factor FoxP3. Treating colitis with resveratrol attenuates the disease by promoting an anti‐inflammatory response which includes decreasing miR‐31, thus preventing the targeting of Treg‐associated FoxP3.