TNF Stabilizes Inflammatory RNA in Synoviocytes

Insights into the inflammation that accompanies rheumatoid arthritis (RA) have led to successful therapies, such as tumor necrosis factor (TNF) inhibitors. TNF activates fibroblast-like synoviocytes (FLS) to express multiple genes. Some researchers have proposed that TNF triggers stabilization of transcripts via the induction of molecular pathways that inhibit the mRNA degradation machinery. This hypothesis stands as part of a bigger question that remains unanswered in molecular biology: Is the mRNA degradation rate per gene constant or does it change over time? If TNF were able to stabilize transcripts, then it could theoretically increase translation efficiency—thereby, increasing protein levels. This hypothesis has important implications for RA because, during the course of chronic synovitis, RA FLS express high levels of potentially pathogenic transcripts.

New research from Konstantinos Loupasakis, MD, a rheumatologist at the Hospital for Special Surgery in New York, and colleagues provides the first insights into genome-wide regulation of mRNA stability in RA FLS. The research, published online July 14 in PLosOne, highlights TNFs’ potential contribution to the dynamic regulation of the mRNA stabilome and, thus, its role in chronic synovitis.¹

“A very interesting finding of our study was the discovery of a temporal switch in the stability states of TNF-induced transcripts in RA FLS,” write the authors in their discussion. “Unstable transcripts dominate the early response to TNF, while during the late TNF response the gene expression program is outbalanced by very stable transcripts. Whereas, transient stabilization of select transcripts can slightly extend transient early expression kinetics in other cell types, such as macrophages, to our knowledge extended stabilization that markedly switches expression kinetics to a sustained pattern is unprecedented.”

The new findings build on the group’s discovery that a single stimulation of FLS with TNF triggers chromatin remodeling. In their current study, the researchers sought to further characterize mRNA stability in the FLS of patients with RA. To do this, they performed a rigorous genome-wide statistical analysis of the genes that were significantly stabilized by TNF. They found that TNF induced a temporal switch by prolonging stabilization of previously unstable transcripts. This TNF-induced mRNA stabilization in RA FLS occurred during the late phase of TNF response. The stabilization allowed for progressive transcript accumulation over three days, as well as sustained expression and late induction of very stable transcripts. Thus, chronic exposure of FLS to TNF appears to increase the mRNA stability status of a wide array of genes, including those with arthritogenic potential.

Previous research has indicated that mitogen-activated protein kinases (MAPKs) play an important role in the regulation of mRNA stability by phosphorylating RNA-binding proteins. The researchers found that this was also the case for TNF-induced stabilization. The TNF-induced stabilization was MAPK-dependent and involved several genes with pathogenic potential, such as IL6, CXCL1, CXCL3, CXCL8/IL8, CCL2, and PTGS2. Thus, TNF appears to induce a late transcriptional program that leads to the expression of gene products that stabilize mRNAs in a selective manner. Because a stable transcript would theoretically be able to support continuously rising expression even in the presence of very low or decreasing rates of transcription, the stabilization of mRNA by TNF can explain the discordance in kinetics between active transcription and total mRNA expression in patients with RA. In this way, TNF contributes to enhanced expression of inflammatory genes and the perpetuation of synovitis.

Lara C. Pullen, PhD, is a medical writer based in the Chicago area.

Reference

1. Loupasakis K, Kuo D, Sokhi UK, et al. Tumor necrosis factor dynamically regulates the mRNA stabilome in rheumatoid arthritis fibroblast-like synoviocytes. PLoS One. 2017 Jul 14;12(7):e0179762. doi:10.1371/journal.pone.0179762. eCollection 2017.