TY - JOUR
T1 - Dual-specificity phosphatase 1 and tristetraprolin cooperate to regulate macrophage responses to lipopolysaccharide
AU - Smallie, Tim
AU - Ross, Ewan A.
AU - Ammit, Alaina J.
AU - Cunliffe, Helen E.
AU - Tang, Tina
AU - Rosner, Dalya R.
AU - Ridley, Michael L.
AU - Buckley, Christopher D.
AU - Saklatvala, Jeremy
AU - Dean, Jonathan L.
AU - Clark, Andrew R.
N1 - Copyright © 2015 The Authors
This is an open-access article distributed under the terms of the CC-BY 3.0 Unported license.
PY - 2015/6/19
Y1 - 2015/6/19
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=84932119466&partnerID=8YFLogxK
UR - https://www.jimmunol.org/content/195/1/277/tab-article-info
U2 - 10.4049/jimmunol.1402830
DO - 10.4049/jimmunol.1402830
M3 - Article
C2 - 26019272
AN - SCOPUS:84932119466
SN - 0022-1767
VL - 195
SP - 277
EP - 288
JO - Journal of Immunology
JF - Journal of Immunology
IS - 1
ER -