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Background: IL-33 is a new tissue-derived cytokine constitutively expressed in epithelial cells and plays a role in sensing damage caused by inflammatory diseases. The function of IL-33 in the esophageal mucosa has not been previously described. Accordingly, we examined the expression of IL-33 and its role in the pathogenesis of reflux esophagitis (RE). Methods: IL-33 in the esophageal mucosa of RE patients and in an in vitro stratified normal esophageal squamous epithelial model was examined at the messenger RNA and protein levels. The correlation of the level of IL-33 and IL-8 or IL-6 was examined. Cell layers were stimulated with bile acids and cytokines. IL-33 was knocked down by small interfering RNA (siRNA). Pharmacological inhibitors and signal transducer and activator of transcription 1 (STAT1) siRNA were used. Results: IL-33 was significantly upregulated in RE patients, and was located in the nuclei of basal and suprabasal layers. Upregulated IL-33 messenger RNA expression was correlated with IL-8 and IL-6 expression. In vitro, IL-33 was upregulated in the nuclei of basal and suprabasal layers by interferon-γ (IFNγ), and the upregulation was aggravated by the combination of deoxycholic acid (DCA) and IFNγ. IL-33 knockdown dampened IFNγ- and DCA-induced IL-8 and IL-6 production. IFNγ-induced IL-33 was inhibited by a Janus kinase inhibitor, a p38 mitogen-activated protein kinase inhibitor, and STAT1 siRNA. Conclusions: Nuclear IL-33 is upregulated in erosive mucosa of RE patients and is correlated with IL-8 and IL-6 levels. The normal esophageal epithelial model enables us to show for the first time that epithelial-cell-derived nuclear but not exogenous IL-33 is located upstream of the production of inflammatory cytokines and can aggravate the inflammation. [ABSTRACT FROM AUTHOR]

Polarization of macrophages to M1 or M2 cells is important for mounting responses against bacterial and helminth infections, respectively. Jumonji domain containing-3 (Jmjd3), a histone 3 Lys27 (H3K27) demethylase, has been implicated in the activation of macrophages. Here we show that Jmjd3 is essential for M2 macrophage polarization in response to helminth infection and chitin, though Jmjd3 is dispensable for M1 responses. Furthermore, Jmjd3 (also known as Kdm6b) is essential for proper bone marrow macrophage differentiation, and this function depends on demethylase activity of Jmjd3. Jmjd3 deficiency affected trimethylation of H3K27 in only a limited number of genes. Among them, we identified Irf4 as encoding a key transcription factor that controls M2 macrophage polarization. Collectively, these results show that Jmjd3-mediated H3K27 demethylation is crucial for regulating M2 macrophage development leading to anti-helminth host responses. [ABSTRACT FROM AUTHOR]

Basophils express major histocompatibility complex class II, CD80 and CD86 and produce interleukin 4 (IL-4) in various conditions. Here we show that when incubated with IL-3 and antigen or complexes of antigen and immunoglobulin E (IgE), basophils internalized, processed and presented antigen as complexes of peptide and major histocompatibility complex class II and produced IL-4. Intravenous administration of ovalbumin-pulsed basophils into naive mice 'preferentially' induced the development of naive ovalbumin-specific CD4+ T cells into T helper type 2 (TH2) cells. Mice immunized in this way, when challenged by intravenous administration of ovalbumin, promptly produced ovalbumin-specific IgG1 and IgE. Finally, intravenous administration of IgE complexes rapidly induced TH2 cells only in the presence of endogenous basophils, which suggests that basophils are potent antigen-presenting cells that 'preferentially' augment TH2-IgE responses by capturing IgE complex. [ABSTRACT FROM AUTHOR]