miR-346 controls release of TNF-alpha protein and stability of its mRNA in rheumatoid arthritis via tristetraprolin stabilization.
Fiche publication
Date publication
janvier 2011
Auteurs
Membres identifiés du Cancéropôle Est :
Dr PFEFFER Sébastien, Pr GOTTENBERG Jacques-Eric
Tous les auteurs :
Semaan N, Frenzel L, Alsaleh G, Suffert G, Gottenberg JE, Sibilia J, Pfeffer S, Wachsmann D
Lien Pubmed
Résumé
TNF-alpha 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-alpha response in macrophages. LPS-activated FLS isolated from RA patients express TNF-alpha 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-alpha mRNA, to be up-regulated in RA FLS in response to LPS, but their repression did not restore mature TNF-alpha expression in FLS. We showed previously that miR-346, which is upregulated in LPS-activated FLS, inhibited Btk expression that stabilized TNF-alpha mRNA. Blocking miR-346 reestablished TNF-alpha expression in activated FLS. Interestingly, transfection of miR-346 in LPS-activated THP-1 cells inhibited TNF-alpha secretion. We also demonstrated that TTP, a RNA binding protein which inhibited TNF-alpha 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-alpha release. These results indicate that miR-346 controls TNF-alpha synthesis by regulating TTP expression.
Référence
PLoS One. 2011;6(5):e19827