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

Publication ,  Journal Article
Ross, EA; Naylor, AJ; O'Neil, JD; Crowley, T; Ridley, ML; Crowe, J; Smallie, T; Tang, TJ; Turner, JD; Norling, LV; Dominguez, S; Perlman, H ...
Published in: Ann Rheum Dis
March 2017

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.

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Published In

Ann Rheum Dis

DOI

EISSN

1468-2060

Publication Date

March 2017

Volume

76

Issue

3

Start / End Page

612 / 619

Location

England

Related Subject Headings

  • p38 Mitogen-Activated Protein Kinases
  • Tristetraprolin
  • Synovial Membrane
  • Serine
  • RNA, Messenger
  • Protein Phosphatase 2
  • Phosphorylation
  • Molecular Targeted Therapy
  • Mice, Inbred C57BL
  • Mice
 

Citation

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Ross, E. A., Naylor, A. J., O’Neil, J. D., Crowley, T., Ridley, M. L., Crowe, J., … Clark, A. R. (2017). Treatment of inflammatory arthritis via targeting of tristetraprolin, a master regulator of pro-inflammatory gene expression. Ann Rheum Dis, 76(3), 612–619. https://doi.org/10.1136/annrheumdis-2016-209424
Ross, E. A., A. J. Naylor, J. D. O’Neil, T. Crowley, M. L. Ridley, J. Crowe, T. Smallie, et al. “Treatment of inflammatory arthritis via targeting of tristetraprolin, a master regulator of pro-inflammatory gene expression.Ann Rheum Dis 76, no. 3 (March 2017): 612–19. https://doi.org/10.1136/annrheumdis-2016-209424.
Ross EA, Naylor AJ, O’Neil JD, Crowley T, Ridley ML, Crowe J, et al. Treatment of inflammatory arthritis via targeting of tristetraprolin, a master regulator of pro-inflammatory gene expression. Ann Rheum Dis. 2017 Mar;76(3):612–9.
Ross, E. A., et al. “Treatment of inflammatory arthritis via targeting of tristetraprolin, a master regulator of pro-inflammatory gene expression.Ann Rheum Dis, vol. 76, no. 3, Mar. 2017, pp. 612–19. Pubmed, doi:10.1136/annrheumdis-2016-209424.
Ross EA, Naylor AJ, O’Neil JD, Crowley T, Ridley ML, Crowe J, Smallie T, Tang TJ, Turner JD, Norling LV, Dominguez S, Perlman H, Verrills NM, Kollias G, Vitek MP, Filer A, Buckley CD, Dean JL, Clark AR. Treatment of inflammatory arthritis via targeting of tristetraprolin, a master regulator of pro-inflammatory gene expression. Ann Rheum Dis. 2017 Mar;76(3):612–619.

Published In

Ann Rheum Dis

DOI

EISSN

1468-2060

Publication Date

March 2017

Volume

76

Issue

3

Start / End Page

612 / 619

Location

England

Related Subject Headings

  • p38 Mitogen-Activated Protein Kinases
  • Tristetraprolin
  • Synovial Membrane
  • Serine
  • RNA, Messenger
  • Protein Phosphatase 2
  • Phosphorylation
  • Molecular Targeted Therapy
  • Mice, Inbred C57BL
  • Mice