Inhibition of Mast Cell Function and Proliferation by mTOR Activator MHY1485

Abstract

Mast cells integrate innate and adaptive immunity and are implicated in pathophysiological conditions, including allergy, asthma, and anaphylaxis. Cross-linking of the high-affinity IgE receptor (Fc epsilon RI) initiates diverse signal transduction pathways and induces release of proinflaminatory mediators by mast cells. In this study, we demonstrated that hyperactivation of mechanistic target of rapamycin (mTOR) signaling using the mTOR activator MHY1485 suppresses Fc epsilon RI-mediated mast cell degranulation and cytokine secretion. MHY1485 treatment increased ribosomal protein S6 kinase (S6K) and eukaryotic translation initiation factor 4E-binding protein 1 (4E-BP1) phosphorylation, which are downstream targets of mTOR complex 1 (mTORC1), but decreased phosphorylation of Akt on mTOR complex 2 (mTORC2) target site serine 473. In addition, this activator decreased beta-hexosaminidase, IL-6, and tumor necrosis factor a (TNF-alpha) release in murine bone marrow-derived mast cells (BMMCs) after Fc epsilon RI stimulation. Furthermore, MHY1485-treated BMMCs showed significantly decreased proliferation when cultured with IL-3. These findings suggested hyperactivation of mTORCl as a therapeutic strategy for mast cell-related diseases.