Inhibition of cholesterol pathway intermediates attenuates IL-33 mediated mast cell cytokine production

Abstract

Abstract Asthma is a growing problem in developed countries, affecting over 24 million individuals in the US alone. Allergic asthma is denoted by a Th2 response that supports IgE-mediated mast cell function and is enhanced by the cytokine IL-33. Although corticosteroids and other treatments are available to help control asthma, many patients have persistent symptoms. In order to meet this unmet need, we investigated the utility of repurposing statin drugs. Statins decrease serum cholesterol by inhibiting HMG-CoA reductase. These drugs have anti-inflammatory effects largely ascribed to loss of isoprenyl lipids downstream of HMGCR. We previously found that statins could decrease IgE-mediated mast cell function. Our current data demonstrate that HMGCR inhibition by simvastatin or isoprenylation blockade with the novel compound FGT-2734 attenuates IL-33 induced mast cell cytokine production in vitro. Statin efficacy for the treatment of allergic asthma has been inconsistent in clinical trials. However, our data suggest that inhibiting isoprenylated signaling molecules may provide a feasible therapeutic target in mast cell-driven disease, and supports the use of statins as a potential adjunct or alternative treatment for individuals with asthma.