Treatment of inflammatory arthritis via targeting of tristetraprolin, a master regulator of pro-inflammatory gene expression

E. A. Ross, A. J. Naylor, J. D. O'Neil, T. Crowley, M. L. Ridley, J. Crowe, T. Smallie, T. J. Tang, J. D. Turner, L. V. Norling, S. Dominguez, H. Perlman, N. M. Verrills, G. Kollias, M. P. Vitek, A. Filer, C. D. Buckley, J. L. Dean, A. R. Clark*

*Corresponding author for this work

Research output: Contribution to journalArticle

Abstract

Objectives Tristetraprolin (TTP), a negative regulator of many pro-inflammatory genes, is strongly expressed in rheumatoid synovial cells. The mitogen-activated protein kinase (MAPK) p38 pathway mediates the inactivation of TTP via phosphorylation of two serine residues. We wished to test the hypothesis that these phosphorylations contribute to the development of inflammatory arthritis, and that, conversely, joint inflammation may be inhibited by promoting the dephosphorylation and activation of TTP. Methods The expression of TTP and its relationship with MAPK p38 activity were examined in non-inflamed and rheumatoid arthritis (RA) synovial tissue. Experimental arthritis was induced in a genetically modified mouse strain, in which endogenous TTP cannot be phosphorylated and inactivated. In vitro and in vivo experiments were performed to test anti-inflammatory effects of compounds that activate the protein phosphatase 2A (PP2A) and promote dephosphorylation of TTP. Results TTP expression was significantly higher in RA than non-inflamed synovium, detected in macrophages, vascular endothelial cells and some fibroblasts and co-localised with MAPK p38 activation. Substitution of TTP phosphorylation sites conferred dramatic protection against inflammatory arthritis in mice. Two distinct PP2A agonists also reduced inflammation and prevented bone erosion. In vitro anti-inflammatory effects of PP2A agonism were mediated by TTP activation. Conclusions The phosphorylation state of TTP is a critical determinant of inflammatory responses, and a tractable target for novel anti-inflammatory treatments.

Original languageEnglish
Pages (from-to)612-619
Number of pages8
JournalAnnals of the Rheumatic Diseases
Volume76
Issue number3
Early online date5 Sep 2016
DOIs
Publication statusPublished - 17 Feb 2017

Bibliographical note

This is an Open Access article distributed in accordance with the terms of the Creative Commons Attribution (CC BY 4.0) license, which permits others to distribute, remix, adapt and build upon this work, for commercial use, provided the original work is properly cited. See: http://creativecommons.org/licenses/by/4.0/

Keywords

  • Cytokines
  • Fibroblasts
  • Inflammation
  • Rheumatoid Arthritis
  • TNF-alpha

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    Ross, E. A., Naylor, A. J., O'Neil, J. D., Crowley, T., Ridley, M. L., Crowe, J., Smallie, T., Tang, T. J., Turner, J. D., Norling, L. V., Dominguez, S., Perlman, H., Verrills, N. M., Kollias, G., Vitek, M. P., Filer, A., Buckley, C. D., Dean, J. L., & Clark, A. R. (2017). Treatment of inflammatory arthritis via targeting of tristetraprolin, a master regulator of pro-inflammatory gene expression. Annals of the Rheumatic Diseases, 76(3), 612-619. https://doi.org/10.1136/annrheumdis-2016-209424