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


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.

Publication DOI:
Divisions: College of Health & Life Sciences
College of Health & Life Sciences > School of Biosciences
Funding Information: This work was supported by program grant 19614 from Arthritis Research UK. We are grateful to Fiona Powrie and Claire Pearson (Oxford) for provision of Il10-/- bone marrow. We have no conflicts of interest with regard to the subjects of this paper. J.D.O.
Additional Information: 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.
Uncontrolled Keywords: Dual-specificity phosphatase 1,Inflammation,Macrophages,Posttranscriptional RNA-binding proteins,Tristetraprolin,Molecular Biology,Cell Biology
Publication ISSN: 1098-5549
Last Modified: 06 May 2024 07:32
Date Deposited: 30 Aug 2019 12:05
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Related URLs: http://www.scop ... tnerID=8YFLogxK (Scopus URL)
https://mcb.asm ... 37/11/e00536-16 (Publisher URL)
PURE Output Type: Article
Published Date: 2017-06-01
Published Online Date: 2017-05-16
Accepted Date: 2017-02-25
Authors: O'Neil, John D.
Ross, Ewan A. (ORCID Profile 0000-0001-5733-9361)
Ridley, Michael L.
Ding, Qize
Tang, Tina
Rosner, Dalya R.
Crowley, Thomas
Malhi, Deepak
Dean, Jonathan L.
Smallie, Tim
Buckley, Christopher D.
Clark, Andrew R.



Version: Published Version

License: Creative Commons Attribution

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