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Published on: January 7, 2019
The oxazolidinone derivative locostatin induces cytokine appeasement
Antoine Ménoret1, Jeremy P McAleer, Soo-Mun Ngoi
1Department 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.
Insights
Locostatin, an inhibitor of Raf kinase inhibitory protein, prevents cytokine storms by inducing T cell anergy. This new therapeutic controls inflammation, sepsis, and autoimmune diseases.
Area of Science:
- Immunology
- Molecular Biology
- Pharmacology
Background:
- Inflammation from autoimmune pathology and sepsis causes severe disease.
- Anti-inflammatory compounds are used to regulate excessive cytokine responses.
- Identifying novel proteins in cytokine storm pathways is crucial.
Purpose of the Study:
- To identify new proteins involved in triggering cytokine storms.
- To investigate the role of Raf kinase inhibitory protein (RIPK) in T cell responses.
- To evaluate locostatin, a RIPK inhibitor, as a potential therapeutic.
Main Methods:
- Utilized a T cell stimulation model for robust immune response.
- Employed comparative proteomic mining to identify differentially mapped proteins.
- Administered locostatin in vivo and assessed T cell anergy and cytokine production.
- Measured Erk phosphorylation and Tumor Necrosis Factor-alpha (TNF-alpha) levels.
Main Results:
- Raf kinase inhibitory protein (RIPK) showed differential mapping after T cell recall.
- Locostatin treatment induced T cell anergy by blocking cytokine production.
- Locostatin reduced Erk phosphorylation and TNF-alpha production in vivo.
- Locostatin inhibited cytokine secretion in both murine and human lymphocytes.
Conclusions:
- Locostatin effectively inhibits cytokine storms by targeting RIPK.
- Locostatin demonstrates therapeutic potential for controlling inflammation, sepsis, and autoimmune diseases.
- Locostatin's efficacy in human lymphocytes supports its broad clinical applicability.
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