Curcumin Ingestion Inhibits Mastocytosis and Suppresses Intestinal Anaphylaxis in a Murine Model of Food Allergy

IgE antibodies and mast cells play critical roles in the establishment of allergic responses to food antigens. Curcumin, the active ingredient of the curry spice turmeric, has anti-inflammatory properties, and thus may have the capacity to regulate Th2 cells and mucosal mast cell function during allergic responses. We assessed whether curcumin ingestion during oral allergen exposure can modulate the development of food allergy using a murine model of ovalbumin (OVA)-induced intestinal anaphylaxis. Herein, we demonstrate that frequent ingestion of curcumin during oral OVA exposure inhibits the development of mastocytosis and intestinal anaphylaxis in OVA-challenged allergic mice. Intragastric (i.g.) exposure to OVA in sensitized BALB/c mice induced a robust IgE-mediated response accompanied by enhanced OVA-IgE levels, intestinal mastocytosis, elevated serum mMCP-1, and acute diarrhea. In contrast, mice exposed to oral curcumin throughout the experimental regimen appeared to be normal and did not exhibit intense allergic diarrhea or a significant enhancement of OVA-IgE and intestinal mast cell expansion and activation. Furthermore, allergic diarrhea, mast cell activation and expansion, and Th2 responses were also suppressed in mice exposed to curcumin during the OVA-challenge phase alone, despite the presence of elevated levels of OVA-IgE, suggesting that curcumin may have a direct suppressive effect on intestinal mast cell activation and reverse food allergy symptoms in allergen-sensitized individuals. This was confirmed by observations that curcumin attenuated the expansion of both adoptively transferred bone marrow-derived mast cells (BMMCs), and inhibited their survival and activation during cell culture. Finally, the suppression of intestinal anaphylaxis by curcumin was directly linked with the inhibition of NF-kappaB activation in curcumin-treated allergic mice, and curcumin inhibited the phosphorylation of the p65 subunit of NF-kappaB in BMMCs. In summary, our data demonstrates a protective role for curcumin during allergic responses to food antigens, suggesting that frequent ingestion of this spice may modulate the outcome of disease in susceptible individuals

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

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 polyphenol ellagic acid exerts anti-inflammatory actions via disruption of store-operated calcium entry (SOCE) pathway activators and coupling mediators

Ellagic acid, a naturally occurring phenol found in a variety of fruits and nuts has been shown to possess anti-inflammatory properties. However, the mechanism of action behind its anti-inflammatory action is unclear. Using human Jurkat T cells, our study examined the effects of ellagic acid (EA) on C

Treatment with curcumin inhibits the expression of intestinal Th2 cytokines in allergic mice.

<p>Mice were fed with OVA and curcumin as depicted in <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0132467#pone.0132467.g001" target="_blank">Fig 1A</a>. (A-H) Expression of jejunal mRNA for various cytokines is shown. Data are representative of 2 independent experiments. * = p<0.05; ** = p<0.01.</p

Exposure to curcumin during OVA-challenge alone suppresses allergic diarrhea, and mast cell expansion and activation.

<p>Mice were fed with OVA and treated with curcumin during OVA-challenge alone as depicted in <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0132467#pone.0132467.g001" target="_blank">Fig 1C</a>. (A) Levels of serum OVA-IgE (1:50 dilution of serum was used for the assay); (B) Percent of mice with diarrhea; (C) CAE⁺ mast cells; (D) and serum mMCP-1 levels are shown. Data are representative of 3 independent experiments. * = p<0.05; ** = p<0.01.</p

Treatment of allergic mice with curcumin inhibits the activation of NF-κB.

<p>(A) Mice were fed with OVA and curcumin and sacrificed as depicted in <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0132467#pone.0132467.g001" target="_blank">Fig 1C</a>. Immunohistochemistry on jejunal sections was performed as described in Materials and Methods. Phospho-relA staining (brown) in jejunal tissue is shown. Phospho-relA-positive mast cells as assessed by morphologic analysis are depicted by red arrows. (B) BMMCs were cultured with or without DNP-IgE and 30 μM curcumin in DMSO and activated in the presence of antigen 24 hours later. 12 hours later, protein was extracted from whole cell lysates and Western blot was performed. Data are representative of three experiments. (C) Quantification of the Western Blot data from B is shown.</p

Curcumin exposure during sensitization alone attenuates allergic diarrhea but has modest effects on antibody production and mast cell activation.

<p>Mice were fed with OVA and treated with curcumin during sensitization only as depicted in <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0132467#pone.0132467.g001" target="_blank">Fig 1B</a>. (A) Levels of serum OVA-IgE (1:100 dilution of serum was used for the assay); (B) Percent of mice with diarrhea; (C) Numbers of CAE⁺ mast cells; (D) and serum mMCP-1 levels are shown.</p