The oxazolidinone derivative locostatin induces cytokine appeasement

J Immunol. 2009 Dec 1;183(11):7489-96. doi: 10.4049/jimmunol.0901414. Epub 2009 Nov 16.


Damaging inflammation arising from autoimmune pathology and septic responses results in severe cases of disease. In both instances, anti-inflammatory compounds are used to limit the excessive or deregulated cytokine responses. We used a model of robust T cell stimulation to identify new proteins involved in triggering a cytokine storm. A comparative proteomic mining approach revealed the differential mapping of Raf kinase inhibitory protein after T cell recall in vivo. Treatment with locostatin, an Raf kinase inhibitory protein inhibitor, induced T cell anergy by blocking cytokine production after Ag recall. This was associated with a reduction in Erk phosphorylation. Importantly, in vivo treatment with locostatin profoundly inhibited TNF-alpha production upon triggering the Ag-specific T cells. This effect was not limited to a murine model because locostatin efficiently inhibited cytokine secretion by human lymphocytes. Therefore, locostatin should be a useful therapeutic to control inflammation, sepsis, and autoimmune diseases.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Anti-Inflammatory Agents / pharmacology*
  • Blotting, Western
  • Chromatography, Liquid
  • Clonal Anergy
  • Cytokines / drug effects*
  • Electrophoresis, Polyacrylamide Gel
  • Extracellular Signal-Regulated MAP Kinases / drug effects
  • Extracellular Signal-Regulated MAP Kinases / metabolism
  • Flow Cytometry
  • Fluorescent Antibody Technique
  • Humans
  • Lymphocyte Activation / immunology
  • Mice
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • Oxazolidinones / pharmacology*
  • Phosphatidylethanolamine Binding Protein / biosynthesis
  • Phosphatidylethanolamine Binding Protein / drug effects*
  • Phosphorylation
  • Proteomics
  • Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization
  • T-Lymphocytes / drug effects*
  • T-Lymphocytes / immunology
  • Tandem Mass Spectrometry
  • Tumor Necrosis Factor-alpha / biosynthesis


  • Anti-Inflammatory Agents
  • Cytokines
  • Oxazolidinones
  • Phosphatidylethanolamine Binding Protein
  • Tumor Necrosis Factor-alpha
  • locostatin
  • Extracellular Signal-Regulated MAP Kinases