Original ArticleMechanisms of Allergic and Immune DiseasesInhibition effect of blunting Notch signaling on food allergy through improving TH1/TH2 balance in mice
Introduction
Food allergy often induces severe allergic diseases complications and seriously affects quality of life. A total of 3% to 4% of adults and 5% of infants have food allergies every year in developed countries.1 The underlying mechanism of this immune disorder currently remains a mystery. Most food allergies are IgE-mediated type 1 immediate hypersensitivity. CD4+ T cells activation and differentiation are key steps in IgE-mediated food allergy.2 The naive CD4+ T cells selectively differentiate into different subtypes, including interferon-γ (IFN-γ)–producing TH1; interleukin (IL)-4, IL-5, IL-13 secreting TH2, IL-17A producing TH17; and inducible regulatory T cell lineages. TH2 polarization and TH2-dominant immune response are major contributors to food allergy.[3], [4] Unfortunately, the mechanism of TH2 polarization induction is still unclear. The differentiation of naive T cells depends on various factors; the recognition of allergen presented to CD4+ T cells by antigen-presenting cells (APCs) is a major effector axis. Many molecules expressed on the surface of T cells and APCs have capacities to drive TH1 or TH2 polarization, such as Toll-like receptors on dendritic cells inducing TH1 polarization5 and the costimulatory molecules OX40 on T cells and OX40L on APCs driving TH2 polarization.6
Recently, the expression of Notch ligands on APCs in concert with Notch receptors on T cells has been found to play a key role in TH1- or TH2-promoting stimuli.[7], [8], [9], [10] Four Notch receptors (Notch1, 2, 3, and 4) and 5 known ligands (Jagged 1 and 2 and Delta-like 1, 3, and 4) have been found in mammals.11 As a highly conserved signaling pathway, Notch signaling is induced when the Notch receptor encounters the ligand. This interaction finally initiates the release of Notch intracellular domain (NICD), which is affected by γ-secretase. Then the NICD translocates to the nucleus to induce the transcription of genes.12 Data from several laboratories revealed that Notch signaling is required in TH2-cell differentiation.[13], [14], [15] However, the role of Notch signaling in TH1 differentiation is still controversial. Many studies have found that Delta-like proteins indeed promoted the differentiation of naive CD4+ T cells into the TH1-cell lineage,[16], [17], [18] but some researchers found that it was not essential to TH1 cell differentiation by using Notch knockout mice.[13], [19] A number of studies have found that Notch signaling plays an important role in a variety of diseases, such as cancer,20 diabetes,21 and asthma,22 but its role in food allergy was not explored.
In this study, the role of Notch signaling in IgE-mediated food allergy was explored. We speculated that Notch signaling was necessary in IgE-mediated food allergy. An ovalbumin-induced IgE-mediated food allergy mouse model was built, and Notch signaling was blunted by FLI-06 and MW167, which inhibited Notch receptor–expressing phase and the γ-secretase–affecting phase, respectively. Then, related indicators of food allergy were examined. The study will define the role of Notch signaling in IgE-mediated food allergy and provide evidence of potential therapy of food allergy.
Section snippets
Mice
Forty-eight female specific pathogen free BALB/c mice (14–18 g) with 4 weeks of age were obtained from Weitong Lihua Inc (Beijing, China) and left to acclimatize for 7days. These mice were provided with fresh water and diet without ovalbumin ad libitum, maintained at a mean (SD) temperature of 23°C (3°C) and a relative humidity of 40% to 70% with a light/dark cycle of 12 hours. All experimental studies were conducted under a protocol approved by the Animal Ethics Committee of China Agricultural
The expressions of NICD and Hes-1 were decreased significantly after being treated with FLI-06 and MW167
Notch signaling works, depending on the release of NICD and the transcription of target genes, such as Hes-1.12 In this study, we detected the expressions of NICD and Hes-1 in MLNs and spleen by quantitative reverse-transcription PCR and Western blotting, respectively. The results indicate that the expressions of NICD and Hes-1 were significantly decreased in both messenger RNA (mRNA) and protein levels in MLNs and spleen after treatment with FLI-06 and MW167 (P < .05). However, there was no
Discussion
In this study, we blunted Notch signaling in mice to explore the role of Notch signaling in IgE-mediated food allergy. We used 2 kinds of inhibitors, FLI-06 and MW167, to suppress Notch signaling in 2 phases of receptor expression and γ-secretase, respectively, and found botch significantly inhibited the expression of NICD and Hes-1 similarly (Fig 1). This finding indicated Notch signaling could be inhibited effectively by suppressing the Notch receptor–expressing phase or the
Acknowledgments
We thank all our colleagues who contributed to this research.
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Disclosures: Authors have nothing to disclose.
Funding Sources: This work was supported by grant 81273077 from the National Natural Science Foundation of China.