The Journal of Experimental Medicine
Fluorescence In Vivo Endomicroscopy
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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) cascade after Toll-like receptor stimulation enables innate immune cells to rapidly activate cytokine gene expression. A balanced response to signals of infectious danger requires that cellular activation is transient. Here, we identify the MAPK phosphatase dual specificity phosphatase 1 (DUSP1) as an essential endogenous regulator of the inflammatory response to lipopolysaccharide (LPS). DUSP1-deficient (DUSP1–/–) bone marrow–derived macrophages showed selectively prolonged activation of p38 MAPK and increased cytokine production. Intraperitoneal challenge of DUSP1–/– mice with LPS caused increased lethality and overshooting production of interleukin (IL)-6 and tumor necrosis factor {alpha}. Transcriptional profiling revealed that DUSP1 controls a significant fraction of LPS-induced genes, which includes IL-6 and IL-10 as well as the chemokines CCL3, CCL4, and CXCL2. In contrast, the expression of the important mediators of endotoxin lethality, interferon {gamma} and IL-12, was not significantly altered by the absence of DUSP1. These data together demonstrate a specific regulatory role of DUSP1 in controlling a subset of LPS-induced genes that determines the outcome of endotoxin shock.


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