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

J Exp Med. 2006 Jan 23;203(1):15-20. doi: 10.1084/jem.20051753. Epub 2005 Dec 27.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Cycle Proteins / genetics
  • Cell Cycle Proteins / immunology*
  • Cytokines / immunology
  • Dual Specificity Phosphatase 1
  • Gene Expression Profiling
  • Gene Expression Regulation
  • Immediate-Early Proteins / deficiency
  • Immediate-Early Proteins / genetics
  • Immediate-Early Proteins / immunology*
  • Lipopolysaccharides
  • Macrophages / immunology*
  • Macrophages / metabolism
  • Mice
  • Mice, Knockout
  • Mitogen-Activated Protein Kinases / metabolism
  • Oligonucleotide Array Sequence Analysis
  • Phosphoprotein Phosphatases / deficiency
  • Phosphoprotein Phosphatases / genetics
  • Phosphoprotein Phosphatases / immunology*
  • Protein Phosphatase 1
  • Protein Tyrosine Phosphatases / deficiency
  • Protein Tyrosine Phosphatases / genetics
  • Protein Tyrosine Phosphatases / immunology*
  • RNA, Messenger / metabolism
  • Shock, Septic / prevention & control*


  • Cell Cycle Proteins
  • Cytokines
  • Immediate-Early Proteins
  • Lipopolysaccharides
  • RNA, Messenger
  • Mitogen-Activated Protein Kinases
  • Phosphoprotein Phosphatases
  • Protein Phosphatase 1
  • Dual Specificity Phosphatase 1
  • Dusp1 protein, mouse
  • Protein Tyrosine Phosphatases