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Background: Direct contact of food proteins with eczematous lesions is thought to be the main cause of epicutaneous sensitization. To further investigate the development and pathogenesis of food allergy in vivo, a good mouse model of epicutaneous sensitization is needed. However, a fundamental problem in that regard is that the optimal age for epicutaneous sensitization of mice is unknown. In this study, we attempted to elucidate that optimal age. Methods: Dorsal skin of wild-type BALB/c female mice (1, 3, 8 and 24 weeks old) was shaved, depilated and tape-stripped. A Finn chamber containing a 20-μl-aliquot of 20-mg/ml (OVA) was applied to the tape-stripped skin on 3 consecutive days/week, for 3 weeks. The body temperature was measured after intraperitoneal OVA challenge. Serum OVA-specific IgE titers and OVA-induced cytokine production by spleen cells were measured by ELISA. Dendritic cells (DCs) that migrated to the draining lymph nodes were quantified by FITC-labeled OVA and flow cytometry. The mRNA expression levels in the dorsal skin were measured by qPCR. Results: A significant age-dependent body temperature decline was observed after OVA challenge. The serum OVA-specific IgE titer, OVA-induced cytokine production (i.e., IL-4, IL-5 and IL-13) by spleen cells, and number of FITC-OVA-engulfing DCs increased with age. In addition, mRNA for IL-33, but not TSLP or IL-25, was significantly induced in the skin by tape-stripping and increased with age. Conclusions: Twenty-four-week-old mice showed the greatest DC migration, Th2 polarization, IgE production and body temperature decline. Skin-derived IL-33 is likely to play key roles in those changes. Keywords: Epicutaneous sensitization, Food allergy, IL-33, Mouse model, Tape stripping

Interleukin-33 (IL-33), a member of the IL-1 cytokine family, is preferentially and constitutively expressed in epithelial cells, and it is especially localized in the cells' nucleus. The nuclear IL-33 is released by necrotic cells after tissue injury and/or trauma, and subsequently provokes local inflammation as an alarmin, like high-mobility group box protein-1 (HMGB-1) and IL-1α. IL-33 mainly activates Th2 cells and such innate-type immune cells as mast cells, basophils, eosinophils and natural helper cells that express IL-33R (a heterodimer of IL-1 receptor-like 1 [IL-1RL1; also called ST2, T1, Der4, fit-1] and IL-1 receptor accessory protein [IL-1RAcP]). That activation causes the cells to produce Th2 cytokines, which contribute to host defense against nematodes. On the other hand, excessive and/or inappropriate production of IL-33 is also considered to be involved in the development of such disorders as allergy. In this review, we summarize current knowledge regarding the pathogenic roles of IL-33 in the development of allergic inflammation by focusing on its effects on innate-type immune cells.

Background: IL-33 is known to induce Th2-type cytokine production by various types of cells through its receptors, ST2 and IL-1RAcP. Polymorphism in the ST2 and/or IL-33 genes was found in patients with atopic dermatitis and asthma, implying that the IL-33/ST2 pathway is closely associated with susceptibility to these diseases. Exposure to allergens through damaged skin is suspected to be a trigger for allergen sensitization, resulting in development of such allergic disorders as asthma and atopic dermatitis. Methods: To elucidate the role(s) of the IL-33/ST2 pathway in asthma in individuals who had been epicutaneously sensitized to an antigen, wild-type and ST2−/− mice were epicutaneously sensitized with ovalbumin (OVA) and then were intranasally challenged with OVA. The degree of airway inflammation, the number of leukocytes and the activities of myeloperoxidase (MPO) and eosinophil peroxidase (EPO) in bronchoalveolar lavage fluids (BALFs), The levels of cytokines and chemokines in lungs and OVA-specific IgE levels in sera were determined by histological analysis, a hemocytometer, colorimetric assay, quantitative PCR or ELISA, respectively. Results: The number of eosinophils in BALFs, the levels of Th2 cytokines and chemoattractants in the lungs and OVA-specific IgE in sera from ST2−/− mice were significantly reduced compared with wild-type mice. Although the number of neutrophils in BALFs and the pulmonary levels of IL-17 were comparable in both mice, the levels of MPO activity in BALFs and neutrophil chemoattractants in the lung were reduced in ST2−/− mice. Conclusions: The IL-33/ST2 pathway is crucial for Th2-cytokine-mediated eosinophilic, rather than Th17-cytokine-mediated neutrophilic, airway inflammation in mice that had been epicutaneously sensitized with antigens and then challenged with antigen.

Background: Treatment with anti-ulcer drugs has been shown to enhance IgE production against food antigens. However, little is known about the immunological effects of cimetidine, a histamine receptor type 2 (H2R) antagonist that is widely used as an anti-ulcer drug, in allergy. Therefore, the present study investigated the role of cimetidine in Th2 immune responses in mice. Methods: BALB/c mice were immunized intraperitoneally with ovalbumin (OVA) with and without cimetidine. The levels of cytokines in supernatants of spleen cells cultured in the presence of OVA for 4 days and the levels of total and OVA-specific IgG1, IgG2a and/or IgE in sera from these mice were determined by ELISA. Results: Administration of cimetidine to OVA-sensitized BALB/c mice promoted Th2 cytokine secretion by OVA-stimulated spleen cells in vitro and increased serum levels of OVA-specific IgE, IgG1 and IgG2a. Conclusions: These results indicate that cimetidine can enhance Th2 responses, suggesting that cimetidine may contribute to IgE production in allergies.

Background: IL-25, which is a member of the IL-17 family, induces Th2 cell differentiation and Th2 cytokine production, contributing to induction of Th2-type immune responses and diseases, as a result of which it suppresses Th1- and Th17-type immune responses. Methods: To elucidate the role of IL-25 in the pathogenesis of IL-17-mediated delayed-type hypersensitivity (DTH), IL-25-deficient mice were sensitized with methylated BSA (mBSA), and then a DTH reaction was induced by mBSA challenge. mBSA-specific T-cell induction was assessed on the basis of cell proliferation and cytokine production. The DTH reaction was evaluated on the basis of tissue swelling, histology and inflammatory mediator expression. Results: IL-25 expression was markedly reduced in local DTH lesions. However, mBSA-specific Th1, Th2 and Th17 cell induction, and the mBSA-induced DTH reaction were comparable in IL-25-deficient and wild-type mice. Conclusions: IL-25 is not essential for differentiation of Th1, Th2 and Th17 cells in the sensitization phase or induction of local inflammation in the elicitation phase of the mBSA-induced DTH reaction.