Presenting Author: Jason R Burchett
, Graduate Research Assistant at Virginia Commonwealth Univ. Sch. of Med.
Abstract:
Allergic asthma is a heterogeneous inflammatory airway disease marked by mast cell and T cell activation and eosinophil infiltration. Treatment options are suboptimal, requiring continual assessment due to breakthroughs of standard regimens. One approach to improved therapy is drug repurposing. Our lab has previously shown that cholesterol-lowering statin drugs can suppress IgE-mediated mast cell function by inhibiting protein isoprenylation, which uses cholesterol pathway intermediates. In addition to IgE, mast cells are also activated by the alarmin IL-33, released by epithelial cells after contact with cellular stressors. We hypothesized that IL-33-mediated mast cell function can be inhibited by disrupting isoprenylation via simvastatin and the dual isoprenyl transferase inhibitor, FGTI-2734. We show that simvastatin and FGTI-2734 suppress IL-33-mediated cytokine mRNA and protein production in mouse mast cells. Simvastatin and FGTI-2735 both suppress IL-33-mediated cytokine production of cultured eosinophils. In an in vivo model, simvastatin and FGTI-2734 also inhibited IL-33-mediated eosinophil and neutrophil infiltration. Simvastatin suppressed IL-33-induced phosphorylation of JNK, ERK1/2, AKT1/2, and NFkB p65, suggesting that statin inhibition occurs at an early step in IL-33 signaling. These findings indicate that targeting the cholesterol pathway via statins or selective isoprenyl transferase inhibitors is a viable target in IL-33-induced allergic inflammation.
Simvastatin suppresses mast cell responses to IL-33 by disrupting isoprenylation
Category
Poster and Podium (Block Symposium)
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Date: May 5 Presentation Time: 11:30 AM to 12:45 PM Room: Exhibit Hall F1