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Dual-specificity phosphatase (DUSP) 1 dephosphorylates and inactivates members of the MAPK superfamily, in particular, JNKs, p38α, and p38β 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 Dusp1(-/-) 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 publication

DOI

10.4049/jimmunol.1402830

Type

Journal article

Journal

Journal of immunology (Baltimore, Md. : 1950)

Publication Date

07/2015

Volume

195

Pages

277 - 288

Addresses

School of Immunity and Infection, College of Medical and Dental Sciences, University of Birmingham, Birmingham B15 2TT, United Kingdom;

Keywords

Macrophages, Animals, Mice, Inbred C57BL, Mice, MAP Kinase Kinase 4, Lipopolysaccharides, Tumor Necrosis Factor-alpha, Mitogen-Activated Protein Kinase 11, Mitogen-Activated Protein Kinase 14, RNA, Messenger, Interleukin-10, Signal Transduction, Gene Expression Regulation, RNA Stability, Phosphorylation, Tristetraprolin, Chemokine CXCL1, Chemokine CXCL2, Dual Specificity Phosphatase 1, Immunity, Innate, Primary Cell Culture