Abstract
KIOM-MA128, a novel herbal medicine, has been reported to exert some beneficial effects on various biological events, such as atopic dermatitis, inflammation and cancer. The aim of this study is to investigate how KIOM-MA128 regulates the allergic response. We measured the activity of β-hexosaminidase and the levels of allergic mediators in the conditioned media of antigen/IgE (Ag/IgE)-activated RBL-2H3 mast cells. We examined the levels of proteins associated with both the FcεRI and arachidonate cascades. Finally, we established the passive cutaneous anaphylaxis (PCA) model in mice to confirm the anti-allergic effects of KIOM-MA128 in vivo. KIOM-MA128 dose-dependently inhibited degranulation and the production of the allergic mediators described above, with no significant cytotoxicity. In the arachidonate cascade, KIOM-MA128 significantly reduced both cytosolic phospholipase A2 (cPLA2) phosphorylation and cyclooxygenase-2 (COX-2) expression. Moreover, in the FcεRI cascade, KIOM-MA128 not only inhibited activation of LYN, FYN and SYK, known as the rate-limiting proteins of the FcεRI cascade, but also suppressed the phosphorylation of ERK, p38 and JNK, which is related to cytokine expression. Finally, 50 to 100 mg/kg KIOM-MA128 significantly attenuated the Ag/IgE-induced PCA reaction in mice. These findings provide novel information and improve our understanding of the anti-allergic effects of KIOM-MA128 on allergic diseases.
Highlights
Mast cells play a critical role in the allergic response, including early- and late-phase reactions [1].A high-affinity receptor for IgE (FcεRI), which is located on the mast cell membrane, interacts with antigen-specific IgE (Ag/IgE)
The findings indicated that KIOM-MA128 did produce cytotoxicity in RBL-2H3 cells
The present study shows that KIOM-MA128 exerts its anti-allergic properties by inhibiting both the FcεRI and arachidonate cascades in Ag/IgE-activated mast cells in vitro and in vivo
Summary
Mast cells play a critical role in the allergic response, including early- and late-phase reactions [1].A high-affinity receptor for IgE (FcεRI), which is located on the mast cell membrane, interacts with antigen-specific IgE (Ag/IgE). The interaction activates the mast cells by initiating molecular signaling pathways, such as the efflux of Ca2+ into the cytosol, and/or phosphorylation of tyrosine kinases, including SYK, LYN and FYN. Cross-linking FcεRI and the Ag/IgE complex activates LYN, which activates SYK. These processes cause the activation of a signaling cascade, including LAT, phospholipase C (PLC) γ, and MAP kinases (MAPKs). Activation of mast cells by the Ag/IgE complex is associated with the secretion of granules containing various allergic mediators, such as β-hexosaminidase, histamines, eicosanoids, serotonin, and pro-inflammatory cytokines and chemokines. Tumor necrosis factor-α, a pro-inflammatory cytokine, induces inflammation during degranulation and recruits various immune cells, causing severe inflammation [2]. The immortalized RBL-2H3 cell line is originated from rat basophilic leukemia cells, and is mostly used for the evaluation of mast cell degranulation and for screening potential anti-allergic agents [3,4]
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