Dual specificity phosphatase 1 (DUSP1) regulates a subset of LPS-induced genes and protects mice from lethal endotoxin shock.
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.
Hammer
Michael
M
Institute of Medical Microbiology, Immunology, and Hygiene, Technical University Munich, 81675 Munich, Germany.
Mages
Jörg
J
Dietrich
Harald
H
Servatius
Angela
A
Howells
Norma
N
Cato
Andrew C B
AC
Lang
Roland
R
D000818:Animals; D018797:Cell Cycle Proteins / Q000235:genetics / Q000276:immunology*; D016207:Cytokines / Q000276:immunology; D054638:Dual Specificity Phosphatase 1; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D017874:Immediate-Early Proteins / Q000172:deficiency / Q000235:genetics / Q000276:immunology*; D008070:Lipopolysaccharides; D008264:Macrophages / Q000276:immunology* / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D020411:Oligonucleotide Array Sequence Analysis; D010749:Phosphoprotein Phosphatases / Q000172:deficiency / Q000235:genetics / Q000276:immunology*; D054645:Protein Phosphatase 1; D017027:Protein Tyrosine Phosphatases / Q000172:deficiency / Q000235:genetics / Q000276:immunology*; D012333:RNA, Messenger / Q000378:metabolism; D012772:Shock, Septic / Q000517:prevention & control*
D018797:Cell Cycle Proteins; D016207:Cytokines; D017874:Immediate-Early Proteins; D008070:Lipopolysaccharides; D012333:RNA, Messenger; D020928:Mitogen-Activated Protein Kinases; D010749:Phosphoprotein Phosphatases; D054645:Protein Phosphatase 1; D054638:Dual Specificity Phosphatase 1; C517020:Dusp1 protein, mouse; D017027:Protein Tyrosine Phosphatases