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miR-346 Controls Release of TNF-a Protein and Stability of Its mRNA in Rheumatoid Arthritis via Tristetraprolin Stabilization
Published: Tuesday, May 17, 2011
Author: Noha Semaan et al.

by Noha Semaan, Laurent Frenzel, Ghada Alsaleh, Guillaume Suffert, Jacques-Eric Gottenberg, Jean Sibilia, Sebastien Pfeffer, Dominique Wachsmann

TNF-a is a major cytokine implicated in rheumatoid arthritis. Its expression is regulated both at the transcriptional and posttranscriptional levels and recent data demonstrated that miRNAs are implicated in TNF-a response in macrophages. LPS-activated FLS isolated from RA patients express TNF-a mRNA but not the mature protein. This prompted us to look for miRNAs which could be implicated in this anti-inflammatory effect. Using a microarray, we found two miRNAs, miR-125b and miR-939 predicted to target the 3'-UTR of TNF-a mRNA, to be up-regulated in RA FLS in response to LPS, but their repression did not restore mature TNF-a expression in FLS. We showed previously that miR-346, which is upregulated in LPS-activated FLS, inhibited Btk expression that stabilized TNF-a mRNA. Blocking miR-346 reestablished TNF-a expression in activated FLS. Interestingly, transfection of miR-346 in LPS-activated THP-1 cells inhibited TNF-a secretion. We also demonstrated that TTP, a RNA binding protein which inhibited TNF-a synthesis, is overexpressed in activated FLS and that inhibition of miR-346 decreases its expression. Conversely, transfection of miR-346 in LPS-activated THP-1 cells increased TTP mRNA expression and inhibited TNF-a release. These results indicate that miR-346 controls TNF-a synthesis by regulating TTP expression.