Search

Intestinal nematode infection induces pulmonary eosinophilia via IL-33, although the mechanism of pulmonary IL-33 induction remains unclear. Because nematode migration damages lungs, we speculated that lung-derived damage-associated molecular patterns (DAMPs) possess an IL-33-inducing activity (IL33ia). Indeed, intra-nasal administration of a lung extract induced IL-33 production in lungs. Additionally, lung extracts increased Il33 mRNA expression in primary lung fibroblasts. Proteomic analysis identified retinoblastoma-binding protein 9 (RBBP9) as a major DAMP with IL33ia. RBBP9 was originally discovered as a protein that provides cells with resistance to the growth inhibitory effect of transforming growth factor (TGF)-β1. Here, we found that stimulation by RBBP9 induced primary fibroblasts to produce prostaglandin E2 (PGE2) that, in turn, induced fibroblasts to produce IL-33. RBBP9-activated fibroblasts expressed mRNAs of cyclooxygenase-2 (COX-2) and PGE2 synthase-1 that convert arachidonic acid to PGE2. Furthermore, they expressed PGE2 receptors E-prostanoid (EP) 2 and EP4. Thus, treatment with a COX-2 inhibitor or EP2 and/or EP4 receptor antagonists inhibited RBBP9-induced IL-33 production. Nematode infection induced pulmonary Il33 mRNA expression, which was inhibited by the COX-2 inhibitor or EP2 and EP4 antagonists, suggesting that nematode infection induced pulmonary Il33 mRNA via PGE2. RBBP9 was expressed constitutively in the lung in the steady state, which did not increase after nematode infection. Finally, we found that Rbbp9 -deficient mice had a significantly diminished capacity to increase pulmonary Il33 mRNA expression following nematode infection. Thus, the PGE2-EP2/EP4 pathway activated by RBBP9 released from damaged lungs is important for pulmonary IL-33 production in nematode-infected animals. [ABSTRACT FROM AUTHOR]

Infections with parasites, especially those involving nematodes that invade tissues, induce a strong Th2-type immune response, which increases immunoglobulin E and eosinophil levels in the blood and tissues. Eosinophils are not effective against all possible helminth infections, but are known to be effective against nematode larvae. In particular, when a host is re-infected by a species of nematode that it previously encountered, the activation of acquired immunity causes robust accumulation and activation of eosinophils that damages the nematode larvae. Eosinophil production and activation processes are mainly induced by interleukin (IL)-5, which is produced by Th2 cells and group 2 innate lymphoid cells, and eosinophils have been shown to generally participate in host defense, inflammation, and immunomodulation. Recently, several papers have reported host defense by non-antigen-specific immune activation, in which group 2 innate lymphoid cells and Th2 cells produce interleukin (IL)-5 and IL-13 in response to IL-33 stimulation. This immune activation is produced by migrating larvae of a species that differs from the species previously encountered. Eosinophils also play an important role in the eradication of migrating larvae. Thus, eosinophils contribute to host defense in both antigen-specific and non-antigen-specific manners. [ABSTRACT FROM AUTHOR]

Endometriosis is an estrogen-dependent disease with symptoms of dysmenorrhea, chronic pain, and infertility that affects 6–10% of women of reproductive age. Medical or surgical therapy, such as administration of an anti-gonadotropin or ovarian cystectomy, provide effective pain relief. However, neither therapy can be used for patients wishing to become pregnant. Despite the high morbidity, the pathogenesis of endometriosis has not been well-elucidated. Several inflammatory cytokines are reported to participate in the onset of endometriosis. Here, we examined the role of interleukin (IL)-1/IL-33 signaling in the development of endometriosis using a mouse model of endometriosis. Endometriotic lesion volume was significantly reduced in Il33 −/− and Il1r1 −/− mice, and almost completely suppressed in Myd88 −/− mice. Mice intraperitoneally administered with an antibody against IL-1 receptor 1 (IL-1R1) or IL-33 developed limited endometriotic lesions. Oral administration of an inhibitor against IL-1R-associated kinase 4 (IRAK4), a downstream signal molecule of MyD88, also suppressed lesion formation. Furthermore, even after the development of cystic lesions the IRAK4 inhibitor prevented the enlargement of lesions. These treatments all significantly reduced cellular proliferation, shown by decreased Ki-67 expression. These results reveal that IL-1/IL-1R1, IL-33/IL-33R and associated downstream signaling molecules are involved in the pathogenesis of endometriosis, and may provide novel therapeutic targets for endometriosis. [ABSTRACT FROM AUTHOR]

The immune responses against helminths have been investigated individually, and it is well-established that infected hosts develop an immunological memory to resist reinfection by the same pathogen. In contrast, it is poorly understood how the host immune system responds to subsequent infection by unrelated parasites after elimination of the first infection. We previously reported that infection of mice with Strongyloides venezuelensis induces the accumulation of group 2 innate lymphoid cells (ILC2s) in the lung. Here, we demonstrated that S. venezuelensis -experienced (Sv-exp) mice became significantly resistant against infection by Nippostrongylus brasiliensis. N. brasiliensis infection induced enhanced accumulation of ILC2s and eosinophils with increased expressions of mRNA for Th2 cytokines in the lungs of Sv-exp mice. The resistance was dependent on ILC2s, and eosinophils but not on CD4+ T cells. Furthermore, pulmonary ILC2s in Sv-exp mice acquired a highly responsive "trained" phenotype; in response to N. brasiliensis infection, they rapidly increased and produced IL-5 and IL-13, which in turn induced the early accumulation of eosinophils in the lungs. IL-33 was required for the accumulation of ILC2s and the resistance of mice against N. brasiliensis infection but insufficient for the induction of trained ILC2s. In conclusion, animals infected with one type of lung-migratory nematodes acquire a specific-antigen-independent resistance to another type of lung-migrating nematodes, providing animals with the capacity to protect against sequential infections with various lung-migratory nematodes. [ABSTRACT FROM AUTHOR]

Helminth infection remains common in developing countries, where residents who suffer from the consequences of such infections can develop serious physical and mental disorders and often persist in the face of serious economic problems. Intestinal nematode infection induces the development of Th2-type immune responses including the B-cell IgE response; additionally, this infection induces an increase in the numbers and activation of various types of effector cells, such as mast cells, eosinophils and basophils, as well as the induction of goblet cell hyperplasia, anti-microbial peptide production and smooth-muscle contraction, all of which contribute to expel nematodes. Innate immunity is important in efforts to eliminate helminth infection; cytokines, including IL-25, IL-33 and thymic stromal lymphopoietin, which are products of epithelial cells and mast cells, induce Th2 cells and group 2 innate lymphoid cells to proliferate and produce Th2 cytokines. Nematodes also facilitate chronic infection by suppression of immune reactions through an increased number of Treg cells. Immunosuppression by parasite infection may ultimately be beneficial for the host animals; indeed, a negative correlation has been found between parasite infection and the prevalence of inflammatory disease in humans. [ABSTRACT FROM AUTHOR]

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]

In the first part of this review, we described the relevant roles of endogenous IL-33 for accumulation of ILC2 and eosinophils even in the lungs of Rag2-/- mice. Type II alveolar epithelial (ATII) cells express IL-33 in their nucleus and infection with Strongyloides venezuelensis induces IL-33 production by increasing the number of ATII cells possibly by the action of chitin. IL-33 from ATII cells induces ILC2 proliferation and at the same time activates them to produce IL-5 and IL-13, which in combination induce lung eosinophilic inflammation, aiding to expel infected worms in the lungs. In the second part, we showed that, although AID-/- mice normally develop Th2 cells and intestinal mastocytosis after infection with S. venezuelensis, they need adoptive transfers of immune sera from S. venezuelensis infected mice to obtain the capacity to promptly expel S. venezuelensis. Thus, intestinal nematode infection induces various Th2 immune responses (e.g., Th2 cell, ILC2, goblet cell hyperplasia, intestinal mastocytosis, smooth muscle cell contraction, local and systemic eosinophilia, and high serum level of IgE and IgG1). However, all of them are not necessary for rapid expulsion of intestinal nematodes. Instead, some combinations of Th2 immune responses are essentially required. [ABSTRACT FROM AUTHOR]

Transgenic mice expressing the mouse interleukin 33 (IL-33) gene driven by a keratin 14 promoter were generated. The skin-selective expression of the IL-33 gene was enhanced, and intense immunofluorescence for IL-33 was evident in the nuclei of the epidermis. Spontaneous itchy dermatitis developed in those mice at 6-8 wk of age in specific pathogen-free conditions. In the lesional skin, the epidermis was thickened and the eosinophils were infiltrated with increased expression of the eosinophil peroxidase and major basic protein genes. Mast cells were also abundant there, and blood histamine and total IgE levels were high. Those phenotypes closely resemble the features of atopic dermatitis. In peripheral blood and lesional skin, IL-5, IL-13, regulated upon activation, normally T-expressed, and presumably secreted (RANTES)/CCL5, and Eotaxin 1/CCL11 were increased, whereas TNF-α, IFN-γ, and thymic stromal lymphopoietin (TSLP) were unaltered. Furthermore, the proportion of group 2 innate lymphoid cells (ILC2s), which produce IL-5, were significantly increased in the lesional skin, peripheral blood, and regional lymph nodes. The dermatitis with eosinophil infiltration was improved by the administration of an anti-IL-5 antibody. These results suggest that the expression of IL-33 in the skin activates an immune response involving ILC2 and that this process might play a crucial role in the pathogenesis of allergic inflammation that is characteristic of atopic dermatitis. [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]

We previously reported that intranasal challenge with ovalbumin (OVA) plus IL-18 induces airway hyperresponsiveness (AHR) and eosinophilic airway inflammation in mice with OVA-specific Th1 cells. These two conditions can be prevented by neutralizing anti-IFN-γ and anti-IL-13 antibodies, respectively. The mice develop AHR and eosinophilic airway inflammation after challenge with OVA plus LPS instead of IL-18 and endogenous IL-18 is known to be involved. In contrast, IL-18 does not facilitate these changes in mice possessing OVA-specific Th2 cells. Here, we investigated whether IL-18 is involved in the development of asthma in mice immunized and challenged with bacterial proteins. Upon intranasal exposure to protein A (SpA) derived from Staphylococcus aureus, mice immunized with SpA exhibited AHR and peribronchial eosinophilic inflammation if IFN-γ or IL-13 were present, respectively. The CD4+ T cells from draining lymph nodes (DLNs) of the SpA-immunized and -challenged mice produced a robust IFN-γ and IL-13 in response to immobilized anti-CD3 antibodies. Treatment with neutralizing anti-IL-18 antibodies prevented asthmatic inflammation concomitant with their impaired potential to express IFN-γ and IL-13. Furthermore, naive mice that received the CD4+ T cells from DLNs of SpA-immunized mice developed airway inflammation depending upon the presence of IL-18. Immunodeficient mice that received human PBMCs, which had been stimulated with SpA in vitro, developed dense peribronchial accumulation of human CD4+ T cells upon SpA challenge. Neutralizing anti-human IL-18 antibodies protected against this airway inflammation. These results suggest the importance of IL-18 for the development of asthmatic inflammation associated with airway exposure to bacterial proteins. [ABSTRACT FROM AUTHOR]

IL-33, a member of the IL-1 family of cytokines, is the ligand for ST2 (IL-33Rα chain). IL-33 has the capacity to induce Th2 cytokine production from Th2 cells, mast cells and basophils, indicating that IL-33 has the potential to induce Th2 cytokine-mediated allergic inflammation of the eye. Thus, we tested the pathological role of IL-33 in allergic conjunctivitis (AC). As reported elsewhere, animals immunized with ragweed pollen (RW)/alum and boosted with RW/PBS developed AC promptly (within 15 min) and conjunctival eosinophilic inflammation after a delay (within 24 h) in response to eye drop challenge with RW. Furthermore, RW-immunized mice, when topically challenged with both RW and IL-33, developed more striking eosinophilia in their conjunctiva without exacerbation of the clinical AC score. This in vivo IL-33 treatment significantly increased the capacity of T cells in the cervical lymph nodes of RW-immunized mice to produce IL-4, IL-5 and IL-13 upon challenge with anti-CD3 and anti-CD28 antibodies in vitro. Furthermore, the infiltrating cells were largely eosinophils and a small proportion of CD4+ T cells, both of which express ST2. We also found that even splenic eosinophils express ST2 and show increased expression in response to IL-5, granulocyte–macrophage colony-stimulating factor (GM-CSF) or IL-33. Eosinophils, stimulated with IL-5 and/or GM-CSF, are responsive to IL-33, which induces production of IL-4 and chemokines. Finally, we showed that conjunctival tissues constitutively express biologically active IL-33, suggesting that IL-33 might play a crucial role in the induction and augmentation of AC. [ABSTRACT FROM PUBLISHER]

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]

Atopic dermatitis (AD) is a common inflammatory skin disease of unknown etiology. Cutaneous infection with microbes such as Staphylococcus aureus and/or skin cleansing with detergent exacerbates clinical AD. Here, we generated an AD animal model by destroying skin barrier function with detergent and subsequent topical application of protein A from S. aureus (SpA). NC/Nga mice, which genetically have reduced skin barrier function, and BALB/c mice having intact skin barrier function, were susceptible to this combination and developed severe and moderate AD, respectively, associated with dermal accumulation of eosinophils and mast cells. Both types of mice showed an increase in serum levels of lL-18, but not IgE. The epidermis of the NC/Nga mice rapidly expressed T helper type 1 (Th1)-associated chemokines, including ligands for CXCR3 and CCR5, after application of both SpA and detergent, but not after application of detergent alone. Although treatment with detergent induced moderate Th1 cell response, additional SpA treatment was a prerequisite for induction of the differentiation of naive T cells toward unique Th1 cells, termed "super Th1 cells," capable of producing both Th1 (IFN-γ) and T helper type 2 cytokine (IL-13), as well as IL-3, and expressing CXCR3 and CCR5. Induction of super Th1 cells required IL-18 stimulation. Blockade of IL-18 prevented AD development, whereas blockade of IL-3 partially prevented AD development, suggesting a contribution of IL-18-dependent IL-3 production to AD with cutaneous mastocytosis. il18-/-BALB/c mice similarly evaded SDS/SpA-induced AD. Thus, IL-18 might be important for the development of infection-associated AD by induction of IL-3 from super Th1 cells. [ABSTRACT FROM AUTHOR]

Toll-like receptors (TLRs) initiate a signalling cascade via association with an adaptor molecule, myeloid differentiation factor 88 (MyD88) and/or TIR domain-containing adaptor inducing-IFN-β (Trif), to induce various pro-inflammatory cytokines for microbial eradication. After stimulation of TLR4 with lipopolysaccharide (LPS), both IL-1β and IL-18 are processed, depending on the activation of caspase-1, although its mechanism remains unclear. ASC is an adapter protein possibly involved in the activation of procaspase-1. To unravel the requirement of ASC, we generated Asc−/– mice. Upon stimulation with LPS, Asc−/– macrophages failed in the processing of procaspase-1 and maturation of pro-IL-1β and pro-IL-18, but normally produced other pro-inflammatory cytokines including TNF-α and IL-6. MyD88−/– and Trif−/– macrophages showed normal activation of caspase-1, demonstrating a dispensable role for MyD88 and Trif. After, LPS-challenged Asc−/– mice lacked serum elevation of IL-1β and IL-18. Moreover, the Asc−/– mice exhibited neither acute liver injury nor lethal shock. These results demonstrate critical roles for ASC in the release of IL-1β/IL-18 via activation of caspase-1 and provide new insights into the inflammatory responses for host defence and diseases. [ABSTRACT FROM AUTHOR]

Recent studies point to glycolipid-enriched membrane (GEM) microdomains as the critical sites for TCR-mediated signal transduction. However, whether the TCR complex is localized in the GEM domain is not well-defined. In the present study, we analyzed localization of the TCR–CD3 complex in the GEM domain by isolating the GEM fraction with sucrose density gradient centrifugation. Although 10% of TCRζ chains was localized in the GEM fraction, most of the TCR complexes were excluded from the GEM before and after T cell activation, and the amount of TCRζ in the GEM was not increased after activation. However, the tyrosine-phosphorylated form of TCRζ was strongly concentrated in the GEM fraction upon TCR engagement. A kinetic study revealed that tyrosine phosphorylation of TCRζ occurred initially in the Triton X-100-soluble membrane fraction followed by the accumulation of phosphorylated TCRζ in the GEM. Thus, these results indicate that phosphorylated TCRζ migrates into the GEM domains on T cell activation. We speculate that the GEM microdomains may function as a reservoir of activation signals from triggered TCR. [ABSTRACT FROM PUBLISHER]

Interleukin (IL)-18 was originally discovered as a factor that enhanced IFN-γ production from anti-CD3-stimulated Th1 cells, especially in the presence of IL-12. Upon stimulation with Ag plus IL-12, naïve T cells develop into IL-18 receptor (IL-18R) expressing Th1 cells, which increase IFN-γ production in response to IL-18 stimulation. Therefore, IL-12 is a commitment factor that induces the development of Th1 cells. In contrast, IL-18 is a proinflammatory cytokine that facilitates type 1 responses. However, IL-18 without IL-12 but with IL-2, stimulates NK cells, CD4+ NKT cells, and established Th1 cells, to produce IL-3, IL-9, and IL-13. Furthermore, together with IL-3, IL-18 stimulates mast cells and basophils to produce IL-4, IL-13, and chemical mediators such as histamine. Therefore, IL-18 is a cytokine that stimulates various cell types and has pleiotropic functions. IL-18 is a member of the IL-1 family of cytokines. IL-18 demonstrates a unique function by binding to a specific receptor expressed on various types of cells. In this review article, we will focus on the unique features of IL-18 in health and disease in experimental animals and humans. [ABSTRACT FROM AUTHOR]