Journal
JOURNAL OF CELLULAR AND MOLECULAR MEDICINE
Volume 18, Issue 11, Pages 2213-2224Publisher
WILEY
DOI: 10.1111/jcmm.12353
Keywords
rheumatoid arthritis; Treg; Th17; miRNA; pro-inflammatory cytokine
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Funding
- National Natural Science Foundation of China [30801046]
- Natural Science Foundation of Jiangsu [BK20141295]
- Jiangsu Government Scholarship for Overseas Studies
- Key Medical Personnel of Zhenjiang
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The imbalance of Th17/Treg cell populations has been suggested to be involved in the regulation of rheumatoid arthritis (RA) pathogenesis; however, the mechanism behind this phenomenon remains unclear. Recent studies have shown how microRNAs (miRNAs) are important regulators of immune responses and are involved in the development of a variety of inflammatory diseases, including RA. In this study, we demonstrated that the frequencies of CD3(+)CD4(+)IL-17(+)Th17 cells were significantly higher, and CD4(+)CD25(+)FOXP3(+) Treg cells significantly lower in peripheral blood mononuclear cells from RA patients. Detection of cytokines from RA patients revealed an elevated panel of pro-inflammatory cytokines, including IL-17, IL-6, IL-1, TNF- and IL-22, which carry the inflammatory signature of RA and are crucial in the differentiation and maintenance of pathogenic Th17 cells and dysfunction of Treg cells. However, the level of miR-21 was significantly lower in RA patients, accompanied by the increase in STAT3 expression and activation, and decrease in STAT5/pSTAT5 protein and Foxp3 mRNA levels. Furthermore, lipopolysaccharide stimulation up-regulated miR-21 expression from healthy controls, but down-regulated miR-21 expression from RA patients. Therefore, we speculate that miR-21 may be part of a negative feedback loop in the normal setting. However, miR-21 levels decrease significantly in RA patients, suggesting that this feedback loop is dysregulated and may contribute to the imbalance of Th17 and Treg cells. MiR-21 may thus serve as a novel regulator in T-cell differentiation and homoeostasis, and provides a new therapeutic target for the treatment of RA.
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