Gain-of-function mutation of tristetraprolin impairs negative feedback control of macrophages in vitro yet has overwhelmingly anti-inflammatory consequences in vivo

John D. O'Neil, Ewan A. Ross, Michael L. Ridley, Qize Ding, Tina Tang, Dalya R. Rosner, Thomas Crowley, Deepak Malhi, Jonathan L. Dean, Tim Smallie, Christopher D. Buckley, Andrew R. Clark*

*Corresponding author for this work

Research output: Contribution to journalArticle

Abstract

The mRNA-destabilizing factor tristetraprolin (TTP) binds in a sequencespecific manner to the 3= untranslated regions of many proinflammatory mRNAs and recruits complexes of nucleases to promote rapid mRNA turnover. Mice lacking TTP develop a severe, spontaneous inflammatory syndrome characterized by the overexpression of tumor necrosis factor and other inflammatory mediators. However, TTP also employs the same mechanism to inhibit the expression of the potent antiinflammatory cytokine interleukin 10 (IL-10). Perturbation of TTP function may therefore have mixed effects on inflammatory responses, either increasing or decreasing the expression of proinflammatory factors via direct or indirect mechanisms. We recently described a knock-in mouse strain in which the substitution of 2 amino acids of the endogenous TTP protein renders it constitutively active as an mRNA-destabilizing factor. Here we investigate the impact on the IL-10-mediated anti-inflammatory response. It is shown that the gain-of-function mutation of TTP impairs IL-10-mediated negative feedback control of macrophage function in vitro. However, the in vivo effects of TTP mutation are uniformly anti-inflammatory despite the decreased expression of IL-10.

Original languageEnglish
Pages (from-to)1-16
Number of pages16
JournalMolecular and Cellular Biology
Volume37
Issue number11
Early online date16 May 2017
DOIs
Publication statusPublished - 1 Jun 2017

Bibliographical note

Copyright © 2017 O'Neil et al.
This is an open-access article distributed under the terms of the Creative Commons Attribution 4.0 International license.

Keywords

  • Dual-specificity phosphatase 1
  • Inflammation
  • Macrophages
  • Posttranscriptional RNA-binding proteins
  • Tristetraprolin

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    O'Neil, J. D., Ross, E. A., Ridley, M. L., Ding, Q., Tang, T., Rosner, D. R., Crowley, T., Malhi, D., Dean, J. L., Smallie, T., Buckley, C. D., & Clark, A. R. (2017). Gain-of-function mutation of tristetraprolin impairs negative feedback control of macrophages in vitro yet has overwhelmingly anti-inflammatory consequences in vivo. Molecular and Cellular Biology, 37(11), 1-16. https://doi.org/10.1128/MCB.00536-16