Lung fibroblasts produce IL-33 in response to stimulation with retinoblastoma-binding protein 9 via production of prostaglandin E2.

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.

IL-33-Induced Atopic Dermatitis-Like Inflammation in Mice Is Mediated by Group 2 Innate Lymphoid Cells in Concert with Basophils.

IL-33 is a proinflammatory cytokine that plays a pivotal role in allergic disorders. In a transgenic mouse expressing IL-33 driven by a keratin-14 promoter (IL33tg), atopic dermatitis (AD)-like inflammation develops spontaneously with the activation of group 2 innate lymphoid cells (ILC2s). However, it remains unknown how effector cells, such as T helper type 2 cells, ILC2s, and basophils, contribute to the inflammatory process induced by IL-33.

Interleukin-18 in Health and Disease.

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.

Nematode-Infected Mice Acquire Resistance to Subsequent Infection With Unrelated Nematode by Inducing Highly Responsive Group 2 Innate Lymphoid Cells in the Lung.

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 induces the accumulation of group 2 innate lymphoid cells (ILC2s) in the lung.

Unique Action of Interleukin-18 on T Cells and Other Immune Cells.

Interleukin (IL)-18 was originally discovered as a factor that enhances interferon (IFN)-γ production by anti-CD3-stimulated Th1 cells, particularly in association with IL-12. IL-12 is a cytokine that induces development of Th1 cells. IL-18 cannot induce Th1 cell development, but has the capacity to activate established Th1 cells to produce IFN-γ in the presence of IL-12.

Host responses to intestinal nematodes.

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.

Expression of IL-33 in ocular surface epithelium induces atopic keratoconjunctivitis with activation of group 2 innate lymphoid cells in mice.

In a transgenic mouse line hK14mIL33tg, with the expression of interleukin-33 (IL-33) driven by a keratin 14 promoter, keratoconjunctivitis developed spontaneously between 18 and 22 weeks of age under specific-pathogen-free conditions. These mice showed blepharitis and corneal impairments, and the histology revealed epithelial thickening in the conjunctiva and the cornea with infiltration of eosinophils, mast cells and basophils. IL-5, IL-13 and CCL11 were abundant in lacrimal fluid in the mice, and the gene expressions of IL-4, IL-5, IL-13, IL-33, Prg2 and Mmcp8 were significantly increased in the cornea.

Epithelial-derived nuclear IL-33 aggravates inflammation in the pathogenesis of reflux esophagitis.

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).

Importance of Both Innate Immunity and Acquired Immunity for Rapid Expulsion of S. venezuelensis.

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.

Pathogenic Th2-type follicular helper T cells contribute to the development of lupus in Fas-deficient mice.

Fas mutant mice are well recognized as autoimmune mouse models, which develop symptoms similar to human systemic lupus erythematosus. Although disease severity in Fas mutant mice is greatly affected by the genetic background, the mechanisms affecting pathological heterogeneity among different strains of Fas mutant mice are poorly understood. In this study, we examined the phenotypic differences between Fas-deficient (Fas (-/-)) mice on the BALB/c and C57BL/6 backgrounds to gain insight into the etiological and pathological heterogeneity of monogenic autoimmune diseases.

Skin-specific expression of IL-33 activates group 2 innate lymphoid cells and elicits atopic dermatitis-like inflammation in mice.

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.

IgG and IgE collaboratively accelerate expulsion of Strongyloides venezuelensis in a primary infection.

The host deploys a subset of immune responses to expel helminths, which differs depending on the nature of the helminth. Strongyloides venezuelensis, a counterpart of the human pathogen S. stercoralis, naturally infects rodents and has been used as an experimental model.

Identification of a novel type 2 innate immunocyte with the ability to enhance IgE production.

Fas (CD95), a member of the tumor necrosis factor receptor superfamily, mediates apoptosis-inducing signals in its expressing cells, especially in self-reactive cells. We recently reported that Fas(-/-) mice with a BALB/c background (BALB/c Fas(-/-) mice) developed blepharitis with allergic inflammation that was accompanied by hyper-IgE production. Here, we found a novel type of immunocyte in the spleen of BALB/c Fas(-/-) mice, which enhanced the production of IgE by B cells in the presence of IL-4 and CD40 signaling in vitro.

Immunotherapeutic applications of IL-18.

To become active and extracellularly released, IL-18 needs post-translational processing by the cytoplasmic enzyme caspase-1, which has high sequence homology with apoptotic cell death-associated enzymes in Caenorhabditis elegans. Furthermore, the receptor for IL-18 shares the signal transduction pathway with the Toll-like receptor, which highly resembles that for the host defense in Drosophila. Since nonvertebrates utilize only innate immunity, it is plausible that IL-18 is an innate immune cytokine.

Fas deficiency in mice with the Balb/c background induces blepharitis with allergic inflammation and hyper-IgE production in conjunction with severe autoimmune disease.

Fas (CD95) is a cell surface death receptor belonging to the tumor necrosis factor receptor superfamily, which mediates apoptosis-inducing signaling when activated by Fas ligand or its agonistic antibody. lpr mice with a loss of apoptosis-inducing function mutation in the Fas gene develop systemic autoimmune disease and lymphadenopathy but not allergic inflammation. In the case of Fas mutations including lpr and knockout (KO), background genes determine the incidence and severity of lymphadenopathy and histopathological manifestation of systemic autoimmunity: MRL-lpr/lpr mice and C57BL/6-lpr/lpr or C57BL/6 Fas KO mice develop severe and minimum disease, respectively.

Generation and characterization of mouse basophils from bone marrow and purification of basophils from spleen.

Basophils are rare circulating granulocytes that originate from progenitor cells in the bone marrow and have been considered important effector cells in IgE-mediated allergic inflammation. Basophils constitute <1% of blood leukocytes and are usually absent or present only in small numbers in tissues. They may, however, be recruited to inflammatory sites when an antigen is present and contribute immediately to hypersensitivity reactions.

A critical role of IL-33 in experimental allergic rhinitis.

Background: We reported previously that serum levels of IL-33 are significantly increased in patients with allergic rhinitis (AR). However, very little is known about the role of IL-33 for the development of AR.

Objective: We thought to develop a novel murine model of ragweed pollen-specific AR and examined the pathologic role for ragweed-induced IL-33 in the development of AR manifestation using IL-33-deficient (il33(-/-)) mice.

Requirement of GATA-binding protein 3 for II13 gene expression in IL-18-stimulated Th1 cells.

Recent reports have revealed that CD4(+) T(h) cell subsets have the ability to alter their gene expression pattern in response to extracellular stimuli. We previously highlighted the plasticity of T(h)1 cells by demonstrating that T(h)1 cells gain the capacity to produce IL-3, IL-9, IL-13 and granulocyte macrophage colony-stimulating factor in response to antigen, IL-2 and IL-18, and based on their unique function, we designated these activated T(h)1 cells as 'super T(h)1 cells'. However, the precise molecular mechanism underlying IL-13 production by super T(h)1 cells has not been elucidated.

Inhibition of surgical trauma-enhanced peritoneal dissemination of tumor cells by human catalase derivatives in mice.

Surgical trauma, which is inevitably associated with the surgical removal of cancer, has been reported to accelerate tumor metastasis. The close association of reactive oxygen species with the trauma and tumor metastasis supports the possibility of using antioxidants for the inhibition of metastasis. To inhibit surgical trauma-enhanced peritoneal dissemination, human catalase (hCAT) derivatives, i.

Contribution of interleukin 18 to the development of infection-associated atopic dermatitis.

Atopic dermatitis (AD) has diverse etiologies. Some AD patients possess pathologically aberrant allergen-specific Th2 cells and resulting allergen-specific IgE, and exposure to the allergen exacerbates the skin lesions. This might be classified into the Th2-type AD.

Basophils as APC in Th2 response in allergic inflammation and parasite infection.

Basophils are important effector cells, which contribute to protection against helminths and execute proinflammatory effector function during allergic inflammation. Basophils are also regulators of Th2 responses in helminth-infected hosts and in allergen-injected animals. Recently, three groups using different experimental systems have shown that basophils are antigen-presenting cells (APC), which induce Th2 cells both in vitro and in vivo.