Immune Netw.  2018 Jun;18(3):e18. 10.4110/in.2018.18.e18.

Inhibition of Mast Cell Function and Proliferation by mTOR Activator MHY1485

• Rakhmanova V
• Jin M
• Shin J

• KMID: 2414558
• DOI: http://doi.org/10.4110/in.2018.18.e18

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 (FcεRI) 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 FcεRI-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 β-hexosaminidase, IL-6, and tumor necrosis factor α (TNF-α) release in murine bone marrow-derived mast cells (BMMCs) after FcεRI 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.

Keyword

Mast cells; High-affinity IgE receptor; Mechanistic target of rapamycin; MHY1485; Cell degranulation; Cell proliferation

MeSH Terms

Adaptive Immunity
Anaphylaxis
Asthma
Cell Degranulation
Cell Proliferation
Hypersensitivity
Immunoglobulin E
Interleukin-3
Interleukin-6
Mast Cells*
Peptide Initiation Factors
Phosphorylation
Ribosomal Protein S6 Kinases
Serine
Signal Transduction
Sirolimus
Tumor Necrosis Factor-alpha
Immunoglobulin E
Interleukin-3
Interleukin-6
Peptide Initiation Factors
Ribosomal Protein S6 Kinases
Serine
Sirolimus
Tumor Necrosis Factor-alpha