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IFN‐γ plays a critical role in host defense against intracellular pathogens. IFN‐γ is produced in the bronchoalveolar lavage fluid of mice infected with Pneumocystis, but the role of IFN‐γ in host defense against Pneumocystis remains controversial. It has been previously reported that although exogenous IFN‐γ has beneficial effects on eradication of Pneumocystis, endogenous IFN‐γ has a negative impact on innate immunity in immunocompromised hosts. Surprisingly, CD4+ T cell‐depleted IFN‐γ deficient (GKO) mice exhibit resistance to Pneumocystis. Alveolar macrophages (AM) from GKO mice exhibit higher expression of macrophage mannose receptor (MMR) and Dectin‐1. Concomitantly, they exhibited greater ability to phagocytize Pneumocystis, and this activity was suppressed by inhibitors of these receptors. Incubation with IFN‐γ resulted in a reduction in both the expression of these receptors on AM and their Pneumocystis‐phagocytic activity. These results indicate that endogenous IFN‐γ facilitates Pneumocystis to escape from host innate immunity by attenuating the phagocytic activity of AM via downregulation of MMR and Dectin‐1. [ABSTRACT FROM AUTHOR]

Basophils produce interleukins (IL)‐4 in response to various stimuli and may contribute to type 2 immune responses to various infections and allergens. We found that resting basophils freshly isolated from mice produce IL‐4 in response to IL‐3 but not to high‐affinity Fc receptor (FcεRI) cross‐linking (CL), yet both required the immunoreceptor tyrosine‐based activation motif (ITAM) containing adaptor Fc receptor γ‐chain (FcRγ), while basophils activated in vitro by IL‐3 become responsive to FcεRI CL. Acquisition of responsiveness to FcεRI CL occurred upon infection with Trichinella spiralis or administration of superantigen. Because cultured basophils return to a quiescent state upon starvation with IL‐3 with surface FcεRI levels unchanged, this acquisition is reversible and probably reflects intracellular events requiring protein synthesis. Interestingly, similar activation‐associated acquisition was observed for responsiveness to other stimuli, including CD200R3 CL, which is known to signal via DAP‐12, and the allergen protease papain. This acquisition of responsiveness to FcεRI CL was inhibited by Jak inhibitor. Thus, the IL‐3 signal bifurcates downstream of Jak, into two distinct pathway, one leading to IL‐4 production and the other to render basophils competent to respond to stimuli dependent on ITAM‐containing adaptors DAP12 and FcRγ for IL‐4 production. [ABSTRACT FROM AUTHOR]

BACKGROUND: Bisphenol A (BPA) is a widespread endocrine-disrupting chemical that can affect humans and animals. OBJECTIVES: We investigated the effects of adult or prenatal exposure to BPA on T-helper ([T.sub.H])1/[T.sub.H]2 immune responses and the mechanisms underlying these effects. METHODS: To evaluate the effects of exposure to BPA in adulthood, male Leishmania major-susceptible BALB/c and -resistant C57BL/6 mice were subcutaneously injected with 0.625, 1.25, 2.5, and 5 [micro]mol BPA 1 week before being infected with L. major. To evaluate prenatal exposure, female mice were given BPA-containing drinking water at concentrations of 1, 10, and 100 nM for 2 weeks, then mated, and given BPA for another week. Male 10-week-old offspring were infected with L. major. Footpad swelling was assessed as a measure of the course of infection. RESULTS: Mice exposed to BPA prenatally or in adulthood showed a dose-dependent increase in footpad swelling after being infected with L. major. Exposure to BPA in adulthood significantly promoted antigen-stimulated production of interleukin (IL)-4, IL-10, and IL-13 but not interferon-[gamma] (IFN-[gamma]). However, mice prenatally exposed to BPA showed increased production of not only IL-4 but also IFN-[gamma]. The percentages of CD[4.sup.+]CD[25.sup.+] cells were decreased in mice exposed to BPA either prenatally or in adulthood. Effects of prenatal BPA exposure were far more pronounced than effects of exposure in adulthood. CONCLUSION: BPA promotes the development of [T.sub.H]2 cells in adulthood and both [T.sub.H]1 and [T.sub.H]2 cells in prenatal stages by reducing the number of regulatory T cells. KEY WORDS: bisphenol A, cytokine, endocrine-disrupting chemicals, prenatal exposure, regulatory T-cells. Environ Health Perspect 116:514-519 (2008). doi:10.1289/ehp.10829 available via http://dx.doi.org/ [Online 29 January 2008], Bisphenol A (BPA), an estrogenic endocrine-disrupting chemical (EDC), has drawn attention because of its potential for human exposure. BPA is widely used, including in dentistry, food packaging, and lacquers to [...]

Signal transducer and activator of transcription (STAT) 6 is a molecule involved in interleukin (IL)-4 and -13 signalling. We investigated the role of STAT6 signalling in Toxoplasma gondii-infected mice using STAT6-deficient (STAT6−/−) and wild-type (WT) mice. A significantly larger number of cysts were recovered from the brain in STAT6−/− than in WT mice on days 28 and 56 post-infection. CD8+ T cells in cerebrospinal fluid and spleen stimulated with T. gondii antigen produced higher levels of interferon (IFN)-γ in WT than in STAT6−/− mice. CD8+ T-cell function, estimated by expression of CD25 and cytotoxic activity, was lower in STAT6−/− than in WT mice. Transfer of CD8+ but not CD4+ T cells, purified from infected WT mice, into STAT6−/− mice successfully prevented formation of cysts in the brain. However, transfer of naïve CD8+ T cells from WT into STAT6−/− mice did not show either activation of CD8+ T cells or a decrease in the number of cysts in the brain. Transfer of splenic adherent cells from WT into STAT6−/− mice induced activation of CD8+ T cells and decreased the number of cysts in the brain. Expression of CD86 on splenic dendritic cells and IL-12 p40 production were weaker in STAT6−/− than in WT mice after T. gondii infection. These results indicate that STAT6 signalling is important in CD8+ T-cell activation, possibly through regulation of antigen-presenting cells, which could suppress T. gondii infection in the brain. [ABSTRACT FROM AUTHOR]

The Fc receptor common γ-chain (FcRγ) is a widely expressed adaptor bearing an immunoreceptor tyrosine-based activation motif (ITAM) that transduces activation signals from various immunoreceptors. We show here that basophils lacking FcRγ developed normally and proliferated efficiently in response to interleukin 3 (IL-3) but were very impaired in IL-3-induced production of IL-4 and in supporting T helper type 2 differentiation. Through its transmembrane portion, FcRγ associated constitutively with the common β-chain of the IL-3 receptor and signaled by recruiting the kinase Syk. Retrovirus-mediated complementation demonstrated the essential function of the ITAM of FcRγ in IL-3 signal transduction. Our results identify a previously unknown mechanism whereby FcRγ functions to 'route' selective cytokine-triggered signals into the ITAM-mediated IL-4 production pathway. [ABSTRACT FROM AUTHOR]

BACKGROUND: Bisphenol A (BPA) is a widespread endocrine-disrupting chemical that can affect humans and animals. OBJECTIVES: We investigated the effects of adult or prenatal exposure to BPA on T-helper (TH)1/TH2 immune responses and the mechanisms underlying these effects. METHODS: To evaluate the effects of exposure to BPA in adulthood, male Leishmania major- susceptible BALB/c and -resistant C57BL/6 mice were subcutaneously injected with 0.625, 1.25, 2.5, and 5 μmol BPA 1 week before being infected with L. major. To evaluate prenatal exposure, female mice were given BPA-containing drinking water at concentrations of 1, 10, and 100 nM for 2 weeks, then mated, and given BPA for another week. Male 10-week-old offspring were infected with L. major. Footpad swelling was assessed as a measure of the course of infection. RESULTS: Mice exposed to BPA prenatally or in adulthood showed a dose-dependent increase in footpad swelling after being infected with L. major. Exposure to BPA in adulthood significantly promoted antigen-stimulated production of interleukin (IL)-4, IL-10, and IL-13 but not interferon-γ (IFN-γ). However, mice prenatally exposed to BPA showed increased production of not only IL-4 but also IFN-γ. The percentages of CD4+CD25+ cells were decreased in mice exposed to BPA either prenatally or in adulthood. Effects of prenatal BPA exposure were far more pronounced than effects of exposure in adulthood. CONCLUSION: BPA promotes the development of TH2 cells in adulthood and both TH1 and TH2 cells in prenatal stages by reducing the number of regulatory T cells. [ABSTRACT FROM AUTHOR]

β-Glucan refers to a heterogeneous group of chemically defined storage polysaccharides containing β-(1,3)- d -linked glucose polymers with branches connected by either β-(1,4) or β-(1,6) glycosidic linkage. To date, an extensive amount of scientific evidence supports their multifunctional biological activities, but their potential involvement in the progression of premalignant lesions remains to be clarified. A4gnt KO mice that lack α1,4- N -acetylglucosamine-capped O -glycans in gastric gland mucin are a unique animal model for gastric cancer because the mutant mice spontaneously develop gastric cancer through hyperplasia-dysplasia-adenocarcinoma sequence. In particular, A4gnt KO mice show gastric dysplasia during 10–20 weeks of age. Here we investigated the putative gastro-protective activity of brown seaweed-derived β-glucan (Laminaran) against development of gastric dysplasia, precancerous lesion for gastric cancer in A4gnt KO mice. The mutant mice at 12 weeks of age were randomly assigned into three treatment groups namely, wildtype control + distilled water (normal control), A4gnt KO mice + distilled water (untreated control), and A4gnt KO mice + 100 mg/kg Laminaran. After 3 weeks, the stomach was removed and examined for morphology and gene expression patterns. In contrast to the untreated control group, administration of Laminaran substantially attenuated gastric dysplasia development and counterbalanced the increased induction in cell proliferation and angiogenesis. Furthermore, Laminaran treatment effectively overcame the A4gnt KO-induced alteration in the gene expression profile of selected cytokines as revealed by real-time PCR analysis. Collectively, our present findings indicate that β-glucan can potentially restrain the development of gastric dysplasia to mediate their tissue-preserving activity. [ABSTRACT FROM AUTHOR]

Differential phase contrast scanning transmission electron microscopy (DPC STEM) is a powerful technique for directly visualizing electromagnetic fields inside materials at high spatial resolution. Electric field observation within ferroelectric materials is potentially possible by DPC STEM, but concomitant diffraction contrast hinders the quantitative electric field evaluation. Diffraction contrast is basically caused by the diffraction-condition variation inside a field of view, but in the case of ferroelectric materials, the diffraction conditions can also change with respect to the polarization orientations. To quantitatively observe electric field distribution inside ferroelectric domains, the formation mechanism of diffraction contrast should be clarified in detail. In this study, we systematically simulated diffraction contrast of ferroelectric domains in DPC STEM images based on the dynamical diffraction theory, and clarify the issues for quantitatively observing electric fields inside ferroelectric domains. Furthermore, we conducted experimental DPC STEM observations for a ferroelectric material to confirm the influence of diffraction contrast predicted by the simulations., (© The Author(s) 2024. Published by Oxford University Press on behalf of The Japanese Society of Microscopy.)

IFN-γ plays a critical role in host defense against intracellular pathogens. IFN-γ is produced in the bronchoalveolar lavage fluid of mice infected with Pneumocystis, but the role of IFN-γ in host defense against Pneumocystis remains controversial. It has been previously reported that although exogenous IFN-γ has beneficial effects on eradication of Pneumocystis, endogenous IFN-γ has a negative impact on innate immunity in immunocompromised hosts. Surprisingly, CD4 + T cell-depleted IFN-γ deficient (GKO) mice exhibit resistance to Pneumocystis. Alveolar macrophages (AM) from GKO mice exhibit higher expression of macrophage mannose receptor (MMR) and Dectin-1. Concomitantly, they exhibited greater ability to phagocytize Pneumocystis, and this activity was suppressed by inhibitors of these receptors. Incubation with IFN-γ resulted in a reduction in both the expression of these receptors on AM and their Pneumocystis-phagocytic activity. These results indicate that endogenous IFN-γ facilitates Pneumocystis to escape from host innate immunity by attenuating the phagocytic activity of AM via downregulation of MMR and Dectin-1., (© 2024 Federation of European Biochemical Societies.)

Antagonists of the 5-hydroxytryptamine (serotonin) 3 receptor (5-HT 3 R) have anti-inflammatory and anti-apoptotic activities, but the detailed, underlying mechanisms are not well understood. We focused on anti-apoptotic activities via 5-HT 3 R signaling to clarify the underlying mechanisms. Mice were administered 5-fluorouracil (5-FU), which induced apoptosis in intestinal epithelial cells. Coadministration with 5-HT 3 R antagonists or agonists tended to decrease or increase the number of apoptotic cells, respectively. In serotonin 3A receptor (5-HT 3A R) null (HTR3A -/- ) mice, the number of apoptotic cells induced by 5-FU was decreased compared with that in wild-type (WT) mice. Bone marrow (BM) transplantation was performed to determine if BM-derived immune cells regulated 5-FU-induced apoptosis, but they were found to be unrelated to this process. Data from 5-HT 3A R/enhanced green fluorescent protein reporter mice revealed that 50% of enterochromaffin (EC) cells expressed 5-HT 3A R, but the number of apoptotic cells induced by 5-FU in the intestinal crypt organoids of HTR3A -/- mice was not altered compared with WT mice. In contrast, plasma 5-HT concentrations in WT mice but not in HTR3A -/- mice administered 5-FU were increased significantly. In conclusion, 5-HT 3 R signaling may enhance 5-HT release, possibly from EC cells intravascularly, or paracrine, resulting in increases in plasma 5-HT concentration, which in turn, enhances apoptotic activities induced by 5-FU.-Mikawa, S., Kondo, M., Kaji, N., Mihara, T., Yoshitake, R., Nakagawa, T., Takamoto, M., Nishimura, R., Shimada, S., Ozaki, H., Hori, M. Serotonin 3 receptor signaling regulates 5-fluorouracil-mediated apoptosis indirectly via TNF-α production by enhancing serotonin release from enterochromaffin cells.

Pneumocystis pneumonia (PCP) occurs frequently in patients with immunodeficiency syndromes, especially AIDS. In order to investigate the role of IFN-gamma on PCP, nude mice deficient in IFN-gamma (GKO nude) and their wild-type ones (WT nude) were infected with murine Pneumocystis. Nine weeks later they were sacrificed, and cytokines in BALF and lung histopathology were compared between them. Cyst burden was greater in GKO than in WT nude mice. Histopathology in the lung was severer and granulomatous lesions were observed more frequently in GKO nude mice. Levels of IL-17 were higher in BALF of GKO than in that of WT nude mice. Greater number of CD4(+) T cells from lungs of infected GKO nude mice produced IL-17 than those from WT ones. These results suggest that deficiency in IFN-gamma induces the differentiation of Th17 and that IL-17 is responsible for inflammatory response in PCP.

The Fc receptor common gamma-chain (FcRgamma) is a widely expressed adaptor bearing an immunoreceptor tyrosine-based activation motif (ITAM) that transduces activation signals from various immunoreceptors. We show here that basophils lacking FcRgamma developed normally and proliferated efficiently in response to interleukin 3 (IL-3) but were very impaired in IL-3-induced production of IL-4 and in supporting T helper type 2 differentiation. Through its transmembrane portion, FcRgamma associated constitutively with the common beta-chain of the IL-3 receptor and signaled by recruiting the kinase Syk. Retrovirus-mediated complementation demonstrated the essential function of the ITAM of FcRgamma in IL-3 signal transduction. Our results identify a previously unknown mechanism whereby FcRgamma functions to 'route' selective cytokine-triggered signals into the ITAM-mediated IL-4 production pathway.

Aims: Neointimal formation after percutaneous coronary intervention (PCI), termed restenosis, limits therapeutic revascularization. Since it is now known that vascular injury involves an inflammatory response, we examined the role of tumour necrosis factor-alpha (TNF-alpha) and interferon-gamma (IFN-gamma) in the neointimal formation after injury., Methods and Results: Control (BALB/c), TNF-alpha-deficient (Tnf(-/-)), IFN-gamma-deficient (Ifng(-/-)), or double-deficient (Tnf(-/-)Ifng(-/-)) mice were subjected to wire-mediated vascular injury of the right femoral artery. Neointimal formation after injury was significantly reduced after the injury in the Tnf(-/-)Ifng(-/-) mice, compared to that in the control, Tnf(-/-), and Ifng(-/-) mice. Immunohistochemical analysis showed that TNF-alpha and IFN-gamma were expressed in neointimal lesions in the control mice, but not in mice with deficiency of the corresponding cytokine. No significant difference in re-endothelialization was observed among these groups. The number of proliferating cell nuclear antigen in the neointimal lesions was significantly decreased in the Tnf(-/-)Ifng(-/-) mice. Bone marrow transplantation experiments revealed that deficiency of TNF-alpha and IFN-gamma specifically in bone marrow cells significantly inhibited neointimal formation after vascular injury., Conclusion: The absence of TNF-alpha and IFN-gamma in bone marrow cells synergistically inhibits neointimal formation following vascular injury, and thus, may provide new insights into the mechanisms underlying restenosis after PCI.