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(1) Background: This study aims to elucidate a novel non-transcriptional action of IRF3 in addition to its role as a transcription factor in mast cell activation and associated allergic inflammation; (2) Methods: For in vitro experiments, mouse bone-marrow-derived mast cells (mBMMCs) and a rat basophilic leukemia cell line (RBL-2H3) were used for investigating the underlying mechanism of IRF3 in mast-cell-mediated allergic inflammation. For in vivo experiments, wild-type and Irf3 knockout mice were used for evaluating IgE-mediated local and systemic anaphylaxis; (3) Results: Passive cutaneous anaphylaxis (PCA)-induced tissues showed highly increased IRF3 activity. In addition, the activation of IRF3 was observed in DNP-HSA-treated mast cells. Phosphorylated IRF3 by DNP-HSA was spatially co-localized with tryptase according to the mast cell activation process, and FcεRI-mediated signaling pathways directly regulated that activity. The alteration of IRF3 affected the production of granule contents in the mast cells and the anaphylaxis responses, including PCA- and ovalbumin-induced active systemic anaphylaxis. Furthermore, IRF3 influenced the post-translational processing of histidine decarboxylase (HDC), which is required for granule maturation; and (4) Conclusion: Through this study, we demonstrated the novel function of IRF3 as an important factor inducing mast cell activation and as an upstream molecule for HDC activity. [ABSTRACT FROM AUTHOR]

Abstract Mast cells play a major role in immunoglobulin E-mediated allergic inflammation, which is involved in asthma, atopic dermatitis, and allergic rhinitis. Nothofagin has been shown to ameliorate various inflammatory responses such as the septic response and vascular inflammation. In this study, we assessed the inhibitory effect of nothofagin on allergic inflammation using cultured/isolated mast cells and an anaphylaxis mouse model. Nothofagin treatment prevented histamine and β-hexosaminidase release by reducing the influx of calcium into the cytosol in a concentration-dependent manner. Nothofagin also inhibited the gene expression and secretion of pro-inflammatory cytokines such as tumor necrosis factor-α and interleukin-4 by downregulating the phosphorylation of Lyn, Syk, Akt and nuclear translocation of nuclear factor-κB. To confirm these effects of nothofagin in vivo , we used a passive cutaneous anaphylaxis mouse model. Topical administration of nothofagin suppressed local pigmentation and ear thickness. Taken together, these results suggest nothofagin as a potential candidate for the treatment of mast cell-involved allergic inflammatory diseases. Highlights • Nothofagin suppressed IgE-induced mast cell degranulation. • Nothofagin downregulated NF-κB translocation through blocking calcium influx. • Nothofagin attenuates vascular permeability induced by mast cell degranulation. • Nothofagin could be used to ameliorate allergic inflammation. [ABSTRACT FROM AUTHOR]