Dual specificity phosphatase 1 (DUSP1) regulates a subset of LPS-induced genes and protects mice from lethal endotoxin shock

doi:10.1084/jem.20051753

Published online 27 December 2005 doi:10.1084/jem.20051753
Rockefeller University Press, 0022-1007 $8.00
JEM, Volume 203, Number 1, 15-20

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BRIEF DEFINITIVE REPORT

Dual specificity phosphatase 1 (DUSP1) regulates a subset of LPS-induced genes and protects mice from lethal endotoxin shock

Michael Hammer¹, Jörg Mages¹, Harald Dietrich¹, Angela Servatius¹, Norma Howells², Andrew C.B. Cato², and Roland Lang¹

¹ Institute of Medical Microbiology, Immunology, and Hygiene, Technical University Munich, 81675 Munich, Germany
² Forschungszentrum Karlsruhe Institute of Toxicology and Genetics, D-76021 Karlsruhe, Germany

CORRESPONDENCE: Roland Lang: Roland.Lang{at}lrz.tum.de

Activation of the mitogen-activated protein kinase (MAPK) cascadeafter Toll-like receptor stimulation enables innate immune cellsto rapidly activate cytokine gene expression. A balanced responseto signals of infectious danger requires that cellular activationis transient. Here, we identify the MAPK phosphatase dual specificityphosphatase 1 (DUSP1) as an essential endogenous regulator ofthe inflammatory response to lipopolysaccharide (LPS). DUSP1-deficient(DUSP1^–/–) bone marrow–derived macrophagesshowed selectively prolonged activation of p38 MAPK and increasedcytokine production. Intraperitoneal challenge of DUSP1^–/–mice with LPS caused increased lethality and overshooting productionof interleukin (IL)-6 and tumor necrosis factor ${alpha}$ . Transcriptionalprofiling revealed that DUSP1 controls a significant fractionof LPS-induced genes, which includes IL-6 and IL-10 as wellas the chemokines CCL3, CCL4, and CXCL2. In contrast, the expressionof the important mediators of endotoxin lethality, interferon ${gamma}$ and IL-12, was not significantly altered by the absence ofDUSP1. These data together demonstrate a specific regulatoryrole of DUSP1 in controlling a subset of LPS-induced genes thatdetermines the outcome of endotoxin shock.

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