Epigenetic Regulation via Altered Histone Acetylation Results in Suppression of Mast Cell Function and Mast Cell-Mediated Food Allergic Responses

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.

The histone deacetylase inhibitor valproic acid attenuates phospholipase Cγ2 and IgE-mediated mast cell activation

“…2E). This result is consistent with a previous report showing that the HDACi TSA also affected FcεRI expression on mast cells depending on the time of exposure 19 . Interestingly, VPA exposure had a differential effect on the expression of other mast cell receptors.…”

“…1F–H). These results indicate that VPA can interfere with cytokine production after mast cell activation through FcεRI, as has been observed with other HDACi, such as sodium butyrate, 21 and TSA 19 . Furthermore, VPA inhibits cytokine production in several cells of the immune response, such as monocytes, macrophages, dendritic cells, and CD4+ T cells, mainly through interfering with the intracellular cell signaling pathways that leads to cytokine production 10 …”

“…2A). This finding shows that the HDACi VPA is an inhibitor of IgE‐mediated mast cell degranulation, like other HDACi such as MGCD0103 and Trichostatin A (TSA) 18,19 . VPA also inhibits degranulation in other immune cells, such as NK cells, in which their cytotoxicity against tumoral cells is restrained 16,20 .…”

“…Previous reports indicate that different HDACi can interfere with IgE‐mediated mast cell degranulation 18,19 . To determine the ability of VPA to affect mast cell degranulation, BMMC were treated with VPA, sensitized with IgE for 18 h, and followed by degranulation induction by FcεRI cross‐linking with TNP‐BSA.…”

“…The mechanism by which VPA alters the cell signaling of immune cells is unclear; although previous reports indicate that VPA attenuates phospholipid cell signaling by an unknown mechanism 34 . It is hypothesized that some HDACi could affect cell signaling through the epigenetic regulation of key molecules 19 . Because of its action as histone deacetylase inhibitor, VPA is able to increase acetylation of histones H2, H3, and H4, leading to modifications in gene expression 35 .…”