MiR-20a regulates ASK1 expression and TLR4-dependent cytokine release in rheumatoid fibroblast-like synoviocytes

ASK1 TLR4型 p38丝裂原活化蛋白激酶 转染 细胞因子 肿瘤坏死因子α 细胞生物学 CXCL10型 炎症 医学 激酶 分子生物学 蛋白激酶A 趋化因子 免疫学 生物 丝裂原活化蛋白激酶激酶 细胞培养 遗传学
作者
Lucas Philippe,Ghada Alsaleh,Angélique Pichot,Eléonore Ostermann,Guy Zuber,Benoı̂t Frisch,Jean Sibilia,Sébastien Pfeffer,Seiamak Bahram,Dominique Wachsmann,Philippe Georgel
出处
期刊:Annals of the Rheumatic Diseases [BMJ]
卷期号:72 (6): 1071-1079 被引量:110
标识
DOI:10.1136/annrheumdis-2012-201654
摘要

Objective To evaluate whether miR-20a belonging to the cluster miR-17–92 is a negative regulator of inflammation in rheumatoid arthritis (RA) fibroblast-like synoviocytes (FLS) by modulating expression of apoptosis signal-regulating kinase (ASK) 1, a key component of the toll-like receptors 4 pathway, upstream of p38 mitogen-activated protein kinase. Methods Evaluation of miR-20a and ASK1 mRNA was performed by RT-qPCR. ASK1 protein expression was assessed by western blotting. Overexpression of miR-20a was performed by transfection of RA FLS and THP-1 cells with miR-20a mimics. Interleukin (IL)-6, CXCL-10, IL-1β and TNF-α release were measured by ELISA. The role of miR-20a in vivo was assessed by IL-6 release from macrophages obtained from mice injected intraperitoneally with vectorised miR-20a mimics. Results We showed that stimulation of RA FLS with lipopolysacharide (LPS) and bacterial lipoproteins (BLP) induces a drop in expression of miR-20a and that this decrease is associated with an upregulation of ASK1 expression. Using transfection of Ask1 3′UTR reporters, we demonstrate that Ask1 is a direct target of miR-20a. Overexpression of miR-20a led to a global decrease in ASK1 protein in BLP- and LPS-activated cells indicating that miR-20a regulates the expression of ASK1 at the translational level. Transfection of miR-20a mimics decreases IL-6 and CXCL10 release by RA FLS and IL-1β and TNF-α by activated THP-1 cells but only in response to LPS. Last, injection of vectorised miR-20a mimics to mice led to a global decrease in ASK1 protein expression and IL-6 secretion in LPS-activated macrophages. Conclusions Our data point toward an important role for miR-20a in the regulation of pro-inflammatory cytokines release, by controlling ASK1 expression in RA FLS.
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