Dual-specificity phosphatase 1 and tristetraprolin cooperate to regulate macrophage responses to lipopolysaccharide

Tim Smallie, Ewan A. Ross, Alaina J. Ammit, Helen E. Cunliffe, Tina Tang, Dalya R. Rosner, Michael L. Ridley, Christopher D. Buckley, Jeremy Saklatvala, Jonathan L. Dean, Andrew R. Clark*

*Corresponding author for this work

Research output: Contribution to journalArticle

Abstract

Dual-specificity phosphatase (DUSP) 1 dephosphorylates and inactivates members of the MAPK superfamily, in particular, JNKs, p38a, and p38b MAPKs. It functions as an essential negative regulator of innate immune responses, hence disruption of the Dusp1 gene renders mice extremely sensitive to a wide variety of experimental inflammatory challenges. The principal mechanisms behind the overexpression of inflammatory mediators by Dusp12/2 cells are not known. In this study, we use a genetic approach to identify an important mechanism of action of DUSP1, involving the modulation of the activity of the mRNA-destabilizing protein tristetraprolin. This mechanism is key to the control of essential early mediators of inflammation, TNF, CXCL1, and CXCL2, as well as the anti-inflammatory cytokine IL-10. The same mechanism also contributes to the regulation of a large number of transcripts induced by treatment of macrophages with LPS. These findings demonstrate that modulation of the phosphorylation status of tristetraprolin is an important physiological mechanism by which innate immune responses can be controlled.

Original languageEnglish
Pages (from-to)277-288
Number of pages12
JournalJournal of Immunology
Volume195
Issue number1
DOIs
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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    Smallie, T., Ross, E. A., Ammit, A. J., Cunliffe, H. E., Tang, T., Rosner, D. R., Ridley, M. L., Buckley, C. D., Saklatvala, J., Dean, J. L., & Clark, A. R. (2015). Dual-specificity phosphatase 1 and tristetraprolin cooperate to regulate macrophage responses to lipopolysaccharide. Journal of Immunology, 195(1), 277-288. https://doi.org/10.4049/jimmunol.1402830