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Extended report
Treatment of inflammatory arthritis via targeting of tristetraprolin, a master regulator of pro-inflammatory gene expression
  1. E A Ross1,
  2. A J Naylor2,
  3. J D O'Neil2,
  4. T Crowley2,
  5. M L Ridley2,
  6. J Crowe3,
  7. T Smallie2,
  8. T J Tang2,
  9. J D Turner2,
  10. L V Norling4,
  11. S Dominguez5,
  12. H Perlman5,
  13. N M Verrills6,
  14. G Kollias7,
  15. M P Vitek8,
  16. A Filer2,
  17. C D Buckley2,
  18. J L Dean3,
  19. A R Clark2
  1. 1Institute of Cardiovascular and Medical Sciences, University of Glasgow, Glasgow, UK
  2. 2Institute of Inflammation and Ageing, University of Birmingham, Birmingham, UK
  3. 3Kennedy Institute of Rheumatology, University of Oxford, Oxford, UK
  4. 4William Harvey Research Institute, QMUL, London, UK
  5. 5Division of Rheumatology, Northwestern University, Chicago, Illinois, USA
  6. 6School of Biomedical Sciences and Pharmacy, University of Newcastle, Callaghan, New South Wales, Australia
  7. 7Division of Immunology, Biomedical Sciences Research Center ‘Alexander Fleming’, Vari, Greece
  8. 8Cognosci Inc., Research Triangle Park, North Carolina, USA
  1. Correspondence to Professor A R Clark, Institute of Inflammation and Ageing, College of Medical and Dental Sciences, University of Birmingham, Edgbaston, Birmingham B15 2TT, UK; a.r.clark{at}


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.

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

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