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

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.

Publication DOI: https://doi.org/10.4049/jimmunol.1402830
Divisions: College of Health & Life Sciences
College of Health & Life Sciences > School of Biosciences
Additional Information: Copyright © 2015 The Authors This is an open-access article distributed under the terms of the CC-BY 3.0 Unported license.
Uncontrolled Keywords: Immunology
Publication ISSN: 1550-6606
Full Text Link:
Related URLs: http://www.scop ... tnerID=8YFLogxK (Scopus URL)
https://www.jim ... ab-article-info (Publisher URL)
PURE Output Type: Article
Published Date: 2015-06-19
Authors: Smallie, Tim
Ross, Ewan A. (ORCID Profile 0000-0001-5733-9361)
Ammit, Alaina J.
Cunliffe, Helen E.
Tang, Tina
Rosner, Dalya R.
Ridley, Michael L.
Buckley, Christopher D.
Saklatvala, Jeremy
Dean, Jonathan L.
Clark, Andrew R.

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