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

The oxazolidinone derivative locostatin induces cytokine appeasement.

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1
Department of Immunology, University of Connecticut Health Center, Farmington, CT 06032, USA.

Abstract

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.

PMID:
19917702
PMCID:
PMC2799496
DOI:
10.4049/jimmunol.0901414
[Indexed for MEDLINE]
Free PMC Article
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