Epigenetic regulation of mast cell function via inhibition of histone acetylation results in suppression of mast cell responses

Abstract

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-a and IL-13. In contrast, pretreatment with either curcumin or TSA resulted in altered cytokine secretion. This was accompanied by decreased expression of FceRI and mast cell degranulation. Interestingly, exposure to non-IgE stimuli such as IL-33, was also affected by TSA treatment. Furthermore, long-term TSA exposure contributed to mast cell apoptosis and a decrease in survival. Further examination revealed a decrease in phospho-relA levels in TSA-treated BMMCs, suggesting that TSA alters transcriptional processes, resulting in decreased NF-kB activation. These data therefore suggest that the epigenetic regulation of mast cell activation during immune responses may occur via regulation of histone acetylation, and that exposure to dietary substances such as curcumin may induce epigenetic modifications that modulate mast cell function.