Fluvastatin enhances IL-33-mediated inflammatory functions in mast cells

Abstract

Abstract Statins are commonly used HMG-CoA reductase (HMGCR) inhibitors prescribed for treating cardiovascular diseases by lowering cholesterol levels. Independent of lowering cholesterol, statins have been shown to inhibit proinflammatory functions in macrophages and T cells. Our lab has previously found that fluvastatin suppresses IgE activation of mouse and human mast cells in vitro, while also protecting C57BL/6 mice from passive systemic anaphylaxis. However, a recent study found that statins can induce proinflammatory cytokines in LPS stimulated macrophages. Due to the conflicting nature of statins, we extended our studies to IL-33, a strong mast cell activator with signaling similar to LPS. In contrast to our findings with IgE signaling, we found that fluvastatin augmented TNF and IL-6 production induced by IL-33 in primary mouse and human mast cells. These effects were dependent on the mitogen SCF, since in its absence the enhancing effects were absent. Mevalonic acid, the product of the HMGCR reaction, reversed fluvastatin effects. Additionally, fluvastatin effects required loss of isoprenoids downstream of HMGCR, since geranylgeranyl pyrophosphate and farnesyl pyrophosphate reduced fluvastatin enhancement of TNF and IL-6 secretion. Fluvastatin enhanced NFκB transcriptional activity in IL-33 stimulated BMMC, and by using an NFκB inhibitor, we found that fluvastatin enhancement of IL-6 and TNF induced by IL-33 is NFκB dependent. This study demonstrates that HMGCR blockade can have either anti or proinflammatory effects on mast cell function, dependent upon the stimulus. These data further reveal the divergent roles for isoprenoid lipids in mast cell function, which may offer new clinical targets for inflammation.