title: miR-346 controls release of TNF-α protein and stability of its mRNA in rheumatoid arthritis via tristetraprolin stabilization.
abstract: TNF-α 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-α response in macrophages. LPS-activated FLS isolated from RA patients express TNF-α 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-α mRNA, to be up-regulated in RA FLS in response to LPS, but their repression did not restore mature TNF-α expression in FLS. We showed previously that miR-346, which is upregulated in LPS-activated FLS, inhibited Btk expression that stabilized TNF-α mRNA. Blocking miR-346 reestablished TNF-α expression in activated FLS. Interestingly, transfection of miR-346 in LPS-activated THP-1 cells inhibited TNF-α secretion. We also demonstrated that TTP, a RNA binding protein which inhibited TNF-α 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-α release. These results indicate that miR-346 controls TNF-α synthesis by regulating TTP expression.
authors: Laboratoire Physiopathologie des Arthrites, EA4438, Université de Strasbourg, UFR Sciences Pharmaceutiques, Illkirch, France.
authors: Noha
authors: N
authors: Semaan
authors: Laurent
authors: L
authors: Frenzel
authors: Ghada
authors: G
authors: Alsaleh
authors: Guillaume
authors: G
authors: Suffert
authors: Jacques-Eric
authors: JE
authors: Gottenberg
authors: Jean
authors: J
authors: Sibilia
authors: Sebastien
authors: S
authors: Pfeffer
authors: Dominique
authors: D
authors: Wachsmann
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