Inhibition of Mast Cell Function and Proliferation by mTOR Activator MHY1485

초록

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?RI) initiates diverse signal transduction pathways and induces release of proinflammatory 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?RI-mediated mast cell degranulation and cytokine secretion. MHY1485 treatment increased S6 kinase (S6K) and 4E-binding protein 1 (4E-BP1) phosphorylation, which are downstream targets of mTOR complex 1 (mTORC1), but decreased phosphorylation of Akt on mTORC2 target site serine 473. In addition, this activator decreased ?-hexosaminidase, interleukin (IL)-6, and tumor necrosis factor ? (TNF-?) release in murine bone marrow-derived mast cells (BMMCs) after Fc?RI stimulation. Furthermore, MHY1485-treated BMMCs showed significantly decreased proliferation when cultured with IL-3. These findings suggested hyperactivation of mTORC1 as a therapeutic strategy for mast cell-related diseases. ? Keywords: mast cells; high-affinity IgE receptor (Fc?RI); mechanistic target of rapamycin (mTOR); MHY1485; degranulation; proliferation?