Dominant suppression of inflammation via targeted mutation of the mRNA destabilizing protein tristetraprolin

Ewan A. Ross, Tim Smallie, Qize Ding, John D. O'Neil, Helen E. Cunliffe, Tina Tang, Dalya R. Rosner, Iva Klevernic, Nicholas A. Morrice, Claudia Monaco, Adam F. Cunningham, Christopher D. Buckley, Jeremy Saklatvala, Jonathan L. Dean, Andrew R. Clark*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review


In myeloid cells, the mRNA-destabilizing protein tristetraprolin (TTP) is induced and extensively phosphorylated in response to LPS. To investigate the role of two specific phosphorylations, at serines 52 and 178, we created a mouse strain in which those residues were replaced by nonphosphorylatable alanine residues. The mutant form of TTP was constitutively degraded by the proteasome and therefore expressed at low levels, yet it functioned as a potent mRNA destabilizing factor and inhibitor of the expression of many inflammatory mediators. Mice expressing only the mutant form of TTP were healthy and fertile, and their systemic inflammatory responses to LPS were strongly attenuated. Adaptive immune responses and protection against infection by Salmonella typhimurium were spared. A single allele encoding the mutant form of TTP was sufficient for enhanced mRNA degradation and underexpression of inflammatory mediators. Therefore, the equilibrium between unphosphorylated and phosphorylated TTP is a critical determinant of the inflammatory response, and manipulation of this equilibrium may be a means of treating inflammatory pathologies.

Original languageEnglish
Pages (from-to)265-276
Number of pages12
JournalJournal of Immunology
Issue number1
Publication statusPublished - 19 Jun 2015

Bibliographical note

Copyright © 2015 The Authors
This is an open-access article distributed under the terms of the CC-BY 3.0 Unported license.


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