Abstract
Mast cells are highly versatile cells that perform a variety of functions depending on the immune trigger, context of activation, and cytokine stimulus. Antigen-mediated mast cell responses are regulated by transcriptional processes that result in the induction of numerous genes contributing to mast cell function. Recently, we also showed that exposure to dietary agents with known epigenetic actions such as curcumin can suppress mast cell-mediated food allergy, suggesting that mast cell responses in vivo may be epigenetically regulated. To further assess the effects of epigenetic modifications on mast cell function, we examined the behavior of bone marrow-derived mast cells (BMMCs) in response to trichostatin A (TSA) treatment, a well-studied histone deacetylase inhibitor. IgE-mediated BMMC activation resulted in enhanced expression and secretion of IL-4, IL-6, TNF-α, and IL-13. In contrast, pretreatment with TSA resulted in altered cytokine secretion. This was accompanied by decreased expression of FcεRI and mast cell degranulation. Interestingly, exposure to non-IgE stimuli such as IL-33, was also affected by TSA treatment. Furthermore, continuous TSA exposure contributed to mast cell apoptosis and a decrease in survival. Further examination revealed an increase in I-κBα and a decrease in phospho-relA levels in TSA-treated BMMCs, suggesting that TSA alters transcriptional processes, resulting in enhancement of I-κBα transcription and decreased NF-κB activation. Lastly, treatment of wild-type mice with TSA in a model of ovalbumin-induced food allergy resulted in a significant attenuation in the development of food allergy symptoms including decreases in allergic diarrhea and mast cell activation. These data therefore suggest that the epigenetic regulation of mast cell activation during immune responses may occur via altered histone acetylation, and that exposure to dietary substances may induce epigenetic modifications that modulate mast cell function.
Highlights
IgE-mediated mast cell activation plays a critical role in the development of allergic responses to food antigens [1, 2]
We previously demonstrated that frequent ingestion of curcumin, which is an active ingredient of the curry spice turmeric, modulates intestinal mast cell function and suppresses the development of mast cell-mediated food allergic responses, suggesting that exposure to dietary components can regulate the development of food allergy [28]
It is extremely likely that the activation and function of mast cells during immune responses is regulated via epigenetic modifications induced by environmental exposure such as dietary antigens [67, 68]
Summary
IgE-mediated mast cell activation plays a critical role in the development of allergic responses to food antigens [1, 2]. Accumulating evidence from a number of studies suggests that the development of the allergic response is tightly regulated via a complex network of interactions between immune cells, genes, and the environment that result in the inhibition of tolerance mechanisms and the promotion of allergic sensitization to environmental allergens [2, 7]. Both genetic polymorphisms and exposure to various environmental stimuli have been shown to increase the susceptibility of developing allergic disease. None of these variables by themselves can account for differences in allergic sensitization in diverse patient subsets, suggesting that the induction of immune activation may be finely regulated via subtle epigenetic interactions involving environmental components and immune genes
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