Antiallergic Effects of Anti-Interleukin-33 are Associated with Suppression of Immunoglobulin Light Chain and Inducible Nitric Oxide Synthase
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Objective We aimed to find novel genes that are significantly induced in allergic mice and that are significantly downregulated with anti-interleukin (IL) 33 treatment. Methods Thirty-six mice were allocated into each of group A (intraperitoneal [i.p.]) sensitized and intranasally challenged to saline solution), group B (sensitized and challenged to ovalbumin), group C (sensitized and challenged with ovalbumin, and null treatment with i.p. saline solution), and group D (sensitized and challenged with ovalbumin, and treatment with anti-IL-33 i.p. injection). We counted the number of nose-scratching in 10 minutes, serum ovalbumin-specific immunoglobulin E (IgE), and titers of cytokines (IL-1, IL-4, IL-5, IL-10, IL-13) in bronchoalveolar lavage fluid. By using one whole lung from each mouse, we performed microarray analysis and real-time polymerase chain reaction. Results Group D showed a significantly reduced nose-scratching events and lower serum ovalbumin-specific IgE compared with groups B and C. All the cytokines in the bronchoalveolar lavage fluid were significantly decreased after anti-IL-33 treatment. Microarray analysis revealed that group B (immunoglobulin free light chain [IgFLC], 89.1 times; nitric oxide synthase [NOS] 2,11.5 times) and group C (IgFLC, 141.6 times; NOS2,11.7 times) had significantly increased expression of IgFLC and NOS2 genes compared with group A. After anti-IL-33 treatment, group D showed significantly decreased expression of both IgFLC (49.3 times) and NOS2 (6.5 times). In real-time polymerase chain reaction, groups B and C had significantly increased expression of these genes (IgFLC, 10.4 times and 29 times, respectively; NOS2, 3.8 times and 4.5 times, respectively). After treatment, group D showed significantly decreased expression of IgFLC (5.0 times) and NOS2 (2.5 times). Conclusion The antiallergic effect of anti-IL-33 can be explained by suppression of IgFLC and NOS2 in a murine model of allergic rhinitis.It is now generally accepted that interleukin 4 (IL4), interleukin 6 (IL6) and interferon-γ (IFNγ) play main roles in the regulation of human IgE synthesis. This concept is based mainly on in vitro data. To obtain corresponding in vivo data, we determined IL4, IL6 and IFNγ by immunoassays in sera collected from 4 atopic patients following a clinical trial of selective IgE apheresis (plasmaimmunoadsorption). This treatment removes several milligrams of IgE from patient’s blood and is suggested to induce strong and isotype-specific activation of the IgE system. Serum IgE levels restored rapidly within 3–5 days after IgE apheresis. However, very low and constant levels of IL4 (from < 50 to 130 pg/ml) and IL6 (from < 300 to 920 pg/ml) were detected in the sera of the treated patients. Serum IFNγ was absent before treatment (concentrations less than 0.5 U/ml) and increased to low but detectable levels (0.90 and 8.05 U/ml) on the day following the last IgE apheresis in 2 of 4 patients. In our opinion, the data presented argue against in vivo participation of IL4 and IL6 in the activation of the human IgE system, at least in atopic patients under constant allergen exposure.
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Interleukin 4 (IL-4) and interferon-gamma (IFN-γ) have been shown to play a role in the regulation of in vitro IgE production by cells from adults. Little information is available regarding the role of these cytokines in influencing IgE production by cells from children. Children ages 3-17 were classified into two groups based upon serum IgE concentrations (>600 U/ml vs. <200 U/ml). Lymphocytes were evaluated for phenotype and IgE production. In vitro IL-4 and IFN-γ production was measured as was the effect of these cytokines on in vitro IgE production by cells obtained from subjects in the two study groups. Children with elevated serum IgE concentrations produced greater amounts of IL-4 than those with lower serum concentrations of IgE. At low dosages of IL-4 (10U) cells from the patients with lower serum IgE concentrations were more sensitive to the effects of IFN-γ, while at higher concentrations of IL-4 (300U) cells from those with higher serum concentrations of IgE were more sensitive to the effects of IFN-γ. The group with higher serum IgE levels had a significantly higher proportion of CD4+ T cells and a greater proportion of cells positive for CD4 and CD29. There are differences in lymphocyte phenotype and IL-4 production in patients with high and normal concentrations of serum IgE. These differences may be important in understanding the basis for different serum IgE concentrations in children.
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Intraperitoneal injection
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Abstract The present study demonstrates that mercuric chloride (HgCl2) induces a striking increase of total serum IgE in Brown Norway (BN) rats. Values up to several milligrams of IgE per milliliter of serum were observed. No antibody specificity was demonstrated for these IgE. Mercuric chloride also potentiated a specific anti-ovalbumin IgE response when the rats were immunized with ovalbumin. The kinetics of the response to HgCl2 was different from that to an antigenic stimulus alone: total IgE increased together with the potentiated anti-ovalbumin IgE antibody response to reach maximum values about 14 days after initiation of HgCl2 injections. The potentiated IgE antibodies represented only an insignificant fraction of total IgE. All these findings were observed in BN but not in Lewis rats. These data show analogies with those reported after parasitic infection in the rat and suggest similar mechanisms of action.
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We correlated serum IgE, interleukin 4 (IL4) and soluble low affinity Fc receptor for IgE (sFc ɛ RII) in atopic and nonatopic children. Serum sFc ɛ RII was significantly higher in atopic than in nonatopic children (0‐2 yr). Serum sFc ɛ RII correlated closely with serum IgE in infants, but not in older children. To study further the characteristics of IgE synthesis in infants, we measured the serum level of IL4, which has been demonstrated to enhance the production of both IgE and sFc ɛ RII in vitro . Serum IL4 was significantly higher in atopic than in nonatopic infants, but there was no significant difference between atopic and nonatopic older children. These results suggest that IL4 plays an important role in the regulation of IgE synthesis in infants and that IgE synthesis in older children might be modulated by other factors.
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Human recombinant interleukin-3 (rIL-3; 10 U/ml) consistently augmented spontaneous IgE synthesis by isolated atopic B cells in vitro, whereas rIL-4 (1-1,000 U/ml) failed to induce IgE synthesis by these cells. Recombinant interferon-gamma (rIFN-gamma) suppressed ongoing IgE production by atopic B cells in a dose-dependent manner. IFN-gamma also inhibited IgE synthesis by a human myeloma cell line (U-266), demonstrating the direct effect of IFN-gamma on the terminal differentiation of IgE-secreting plasma cells. IL-3 and IFN-gamma from different sources displayed the same effects on IgE synthesis. Neutralizing antibodies toward IL-3 or IFN-gamma abolished their activities toward IgE synthesis, supporting the specificity of the effect of these cytokines. The quantity of endogenous IFN-gamma produced by stimulated T cells was significantly decreased in atopic patients compared to nonatopic controls, which might be responsible for the propensity of a high blood IgE level in atopic patients.
Interferon type II
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Цель. Оценить цитокин-продуцирующую активность мононуклеарных клеток периферической крови пациентов с аллергическим ринитом (АР), сенсибилизированных к клещам домашней пыли, для установления дополнительных дифференциальных критериев, которые позволили бы разграничить IgE-зависимую и IgE-независимую форму заболевания, что в дальнейшем может служить научным обоснованием к использованию новых подходов к лечению заболевания и оценке эффективности терапии аллергического ринита.Материалы и методы. В исследование было включено 60 человек с аллергическим ринитом в возрасте 20–60 лет. По уровню общего IgE (при пороговом значении IgE>100 kU/L) пациенты были разделены на две группы: с IgE-зависимой и IgE-независимой формой АР. Для исследования проводили определение спонтанной и митогениндуцированной продукции цитокинов IL-2, g-ИФН, IL4, IL5, IL13, IL-10 и TGF-β мононуклеарами периферической крови в условиях in vitro.Результаты и обсуждение. Установлено, что для пациентов с IgЕ-зависимой формой АР характерно снижение спонтанной и митогениндуцированной продукции цитокинов IL-2 и g-ИФН, повышение уровня Th2-цитокинов – IL4, IL5 и IL13 и снижение Treg-цитокинов – IL-10 и TGF-β. У пациентов же с IgE-независимой формой АР не было установлено достоверных изменений в уровне ИФН-g, а также наблюдалось повышение уровня спонтанной и индуцированной продукции клетками TGF-b.Заключение. В условиях in vitro наблюдается нарушение спонтанной и митоген-активированной продукции цитокинов мононуклеарами периферической крови как пациентов с IgЕ-зависимой формой, так и с IgЕ-независимой формой АР с сенсибилизацией к клещам домашней пыли. В группе пациентов с IgЕ-зависимой формой заболевания эти изменения были более выраженными. Purpose. To evaluate the cytokine-producing activity of peripheral blood mononuclear cells of patients with AR sensitized to house dust mites to reveal additional differential criteria that would allow to distinguish between the IgE-dependent and IgE-independent form of the disease, which could later become the target for new approaches to treatment and evaluation of the effectiveness of treatment of allergic rhinitis.Materials and methods. The study included 60 patients with AR aged 20–60 years. According to the level of total IgE (IgE>100), patients were divided into two groups, according to IgE-dependent and IgE-independent form of AR. For the study, there was determined the spontaneous and mitogen-induced production of cytokines IL-2, g-IFN, IL4, IL5, IL13, IL-10 and TGF-β by peripheral blood mononuclear cells in vitro.Results and discussion. According to the study, patients with IgE-dependent form of AR are characterized by the decrease of spontaneous and mitogen-induced production of cytokines IL-2 and g-IFN, the increase of Th2 cytokines – IL4, IL5, and IL13, and the decrease of Treg cytokines – IL-10 and TGF-β. The difference was that in patients with IgE-independent form of AR, there were no significant changes in the level of IFN-g, and there was the increase of the level of spontaneous and induced production by TGF-b cells.Conclusion. There is a violation of spontaneous and mitogen-activated production of cytokines by peripheral blood mononuclear cells in vitro in the group of patients with IgE-dependent form and IgE-independent form of AR with sensitization to house dust mites. In the group of patients with IgE-dependent form, these changes were more pronounced.
Interleukin 13
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