The oxazolidinone derivative locostatin induces cytokine appeasement.
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.
Ménoret
Antoine
A
Department of Immunology, University of Connecticut Health Center, Farmington, CT 06032, USA.
McAleer
Jeremy P
JP
Ngoi
Soo-Mun
SM
Ray
Swagatam
S
Eddy
Nicholas A
NA
Fenteany
Gabriel
G
Lee
Seung-Joo
SJ
Rossi
Robert J
RJ
Mukherji
Bijay
B
Allen
David L
DL
Chakraborty
Nitya G
NG
Vella
Anthony T
AT
D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology*; D015153:Blotting, Western; D002853:Chromatography, Liquid; D017635:Clonal Anergy; D016207:Cytokines / Q000187:drug effects*; D004591:Electrophoresis, Polyacrylamide Gel; D048049:Extracellular Signal-Regulated MAP Kinases / Q000187:drug effects / Q000378:metabolism; D005434:Flow Cytometry; D005455:Fluorescent Antibody Technique; D006801:Humans; D008213:Lymphocyte Activation / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D023303:Oxazolidinones / Q000494:pharmacology*; D049488:Phosphatidylethanolamine Binding Protein / Q000096:biosynthesis / Q000187:drug effects*; D010766:Phosphorylation; D040901:Proteomics; D019032:Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization; D013601:T-Lymphocytes / Q000187:drug effects* / Q000276:immunology; D053719:Tandem Mass Spectrometry; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis
D000893:Anti-Inflammatory Agents; D016207:Cytokines; D023303:Oxazolidinones; D049488:Phosphatidylethanolamine Binding Protein; D014409:Tumor Necrosis Factor-alpha; C529490:locostatin; D048049:Extracellular Signal-Regulated MAP Kinases