IgE-induced mast cell function is suppressed by antagonizing isoprenylation or Ras activation

Abstract

Abstract Mast cells are tissue resident innate immune cells activated by IgE and other ligands. Upon activation they release histamine, cytokines, chemokines, proteases, and lipid mediators evoking allergic symptoms. New ways of targeting mast cells could greatly benefit allergic disease therapy. We previously found that statin drugs reduced IgE-mediated inflammation in vitro and in vivo by inhibiting production of the isoprenoid lipid geranylgeranyl pyrophosphate. However, this suppression was dependent on genetic background. To overcome this limitation, we tested a dual farnesyl and geranylgeranyl transferase inhibitor (FGTI 2734). Using mouse mast cells, we show that FGTI 2734 reduced IgE-mediated degranulation and cytokine production similar to statin effects. Unlike statins, FGTI 2734 did not show a significant difference in IC50 based on genetic background. Furthermore, FGTI 2734 suppressed IgE-mediated systemic anaphylaxis in vivo. Ras GTPases are important for mast cell function and among the signaling proteins modified by isoprenylation. We show that Pan-Ras inhibitors can mimic statin and FGTI 2734 effects on cytokine production in mouse mast cells. These data indicate that dual farnesyl and geranylgeranyl transferase inhibition may be effective in suppressing IgE-induced inflammation, possibly due by disrupting Ras-mediated signals.