CDK4/6 inhibitor palbociclib suppresses IgE-mediated mast cell activation

Abstract

Background Mast cell activation causes degranulation and release of cytokines, thereby promoting inflammation. The aim of this study was to investigate the inhibitory effect of CDK4/6 inhibition on mast cell activation in vitro and in vivo. Methods RBL-2H3 rat basophilic leukemia cells (BLCs) and mouse bone marrow-derived mast cells (BMMCs) were sensitized with anti-dinitrophenol (DNP) immunoglobulin (Ig)E antibodies, stimulated with DNP-human serum albumin (HSA) antigens, and treated with the CDK4/6 inhibitor palbociclib. Histological stains were applied to reveal cytomorphological changes. Murine IgE-mediated passive cutaneous anaphylaxis (PCA) and ovalbumin (OVA)-induced active systemic anaphylaxis (ASA) models were used to examine palbociclib effects on allergic reactions in vivo. Western blots were performed to detect the expression of cell signaling molecules associated with mast cell activation. Results Activated BLCs and BMMCs released copious granule-related mediators (histamine and β-hexosaminidase), which was reduced by palbociclib in a concentration-dependent manner. Palbociclib inhibited expression of the mast cell activation marker CD63 in activated BLCs and inhibited granule release (visualized with toluidine blue staining) while preventing morphological changes, (elongated shape maintained) and filamentous actin (F-actin) reorganization. Palbociclib suppressed molecular Lyn and/or mitogen-activated protein kinase (MAPK) signaling associated with mast cell activation in stimulated BLCs and attenuated allergic reactions in PCA mice dose dependently. Palbociclib attenuated body temperature reduction and diminished serum histamine levels in ovalbumin OVA-challenged ASA mice. Conclusion Palbociclib suppresses IgE-mediated mast cell activation in vitro and in vivo, suggesting that it may be developed into a therapy for mast cell-mediated allergic diseases via inhibition of mast cell degranulation.

Inhibition of c-Fos expression attenuates IgE-mediated mast cell activation and allergic inflammation by counteracting an inhibitory AP1/Egr1/IL-4 axis

“…Our results showing that T-5224 reduced FcεRI-mediated degranulation in MCs were similar to previously reported effects of palbociclib (cyclin-dependent kinase inhibitor) and tozasertib (Aurora kinase inhibitor) [ 22 , 52 ]. Mechanistically, T-5224 decreased IgE/Ag-induced expression of EGR1 and IL4 and also blocked MAPK activation in activated MCs.…”

“…The spun-down cells were cultured (0.5 × 10 6 nucleated cells/mL) in RPMI 1640 media supplemented with 10% fetal bovine serum, penicillin (100 U/mL), streptomycin (100 μg/mL), sodium pyruvate (10 mM), l -glutamine (2 mM), 4-(2-hydroxyethyl)-piperazine ethane sulfonic acid (10 mM), and recombinant stem cell factor and IL-3 (10 ng/mL each). After ~ 5 weeks in culture, BMMC purity was ~ 95%, as determined by flow cytometry of cell-surface CD117 and FcεRI [ 22 ].…”

Flavoring agent dihydrocoumarin alleviates IgE-mediated mast cell activation and allergic inflammation

“…Notably, the adverse reactions associated with antihistamines include dry mouth, tachycardia, gastrointestinal dysfunction, and cardiovascular dysfunction. 23 Pharmaceutical developers hope to develop natural anti-allergic compounds that can inhibit IgE-mediated MC activation without undesirable effects. Natural compounds that have been reported to down-regulate allergic responses via the inhibition of FcεRI expression or the FcεRI-IgE interaction blockade include phlorotannins found in brown seaweed, polyphenols found in green tea (especially EGCG), chitooligosaccharides derived from crustacean chitin, and the fungal metabolite aspercyclide A.…”

Salvinorin A inhibits ovalbumin‐stimulated allergic rhinitis and RBL‐2H3 cells degranulation

“…Degranulation is a marker of mast cell activation and the release of inflammatory mediators [ 24 ]. Cytoplasmic granules contain the degranulation indicators β‐hexosaminase and histamine [ 25 ]. IL‐4 is an indispensable molecule in allergic reactions, inducing homotypic conversion to IgE, up‐regulating adhesion molecules and promoting eosinophil migration [ 26 , 27 ].…”