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: Noha Semaan, Laurent Frenzel, Ghada Alsaleh, Guillaume Suffert, Jacques-Eric Gottenberg, Jean Sibilia, Sebastien Pfeffer, Dominique Wachsmann
• Journal: PloS one (PLoS One) Vol. 6 Issue 5 Pg. e19827 ( 2011) ISSN: 1932-6203 [Electronic] United States
• PMID: 21611196 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Lipopolysaccharides
• MIRN125 microRNA, human
• MIRN346 microRNA, human
• MicroRNAs
• RNA, Antisense
• RNA, Messenger
• Tristetraprolin
• Tumor Necrosis Factor-alpha
• Protein-Tyrosine Kinases
• Agammaglobulinaemia Tyrosine Kinase
• BTK protein, human

Topics

• Agammaglobulinaemia Tyrosine Kinase
• Arthritis, Rheumatoid (genetics, pathology)
• Cell Line
• Fibroblasts (drug effects, metabolism, pathology)
• Gene Expression Regulation
• Humans
• Lipopolysaccharides (pharmacology)
• MicroRNAs (genetics, metabolism)
• Models, Biological
• Protein Stability (drug effects)
• Protein-Tyrosine Kinases (metabolism)
• RNA Stability (drug effects)
• RNA, Antisense (metabolism)
• RNA, Messenger (genetics, metabolism)
• Reverse Transcriptase Polymerase Chain Reaction
• Synovial Fluid (cytology)
• Transfection
• Tristetraprolin (metabolism)
• Tumor Necrosis Factor-alpha (biosynthesis, genetics, metabolism)