Antigen-induced Eosinophil Research Articles

Helminth antigens counteract a rapid high-fat diet-induced decrease in adipose tissue eosinophils.

Brown adipose tissue (BAT) activation and white adipose tissue (WAT) beiging can increase energy expenditure and have the potential to reduce obesity and associated diseases. The immune system is a potential target in mediating brown and beige adipocyte activation. Type 2 and anti-inflammatory immune cells contribute to metabolic homeostasis within lean WAT, with a prominent role for eosinophils and interleukin (IL)-4-induced anti-inflammatory macrophages. We determined eosinophil numbers in epididymal WAT (EpAT), subcutaneous WAT (ScAT) and BAT after 1 day, 3 days or 1 week of high-fat diet (HFD) feeding in C57Bl/6 mice. One day of HFD resulted in a rapid drop in eosinophil numbers in EpAT and BAT, and after 3 days, in ScAT. In an attempt to restore this HFD-induced drop in adipose tissue eosinophils, we treated 1-week HFD-fed mice with helminth antigens from Schistosoma mansoni or Trichuris suis and evaluated whether the well-known protective metabolic effects of helminth antigens involves BAT activation or beiging. Indeed, antigens of both helminth species induced high numbers of eosinophils in EpAT, but failed to induce beiging. In ScAT, Schistosoma mansoni antigens induced mild eosinophilia, which was accompanied by slightly more beiging. No effects were observed in BAT. To study type 2 responses on brown adipocytes directly, T37i cells were stimulated with IL-4. This increased Ucp1 expression and strongly induced the production of eosinophil chemoattractant CCL11 (+26-fold), revealing that brown adipocytes themselves can attract eosinophils. Our findings indicate that helminth antigen-induced eosinophilia fails to induce profound beiging of white adipocytes.

The Inhibitory Effect of S-777469, a Cannabinoid Type 2 Receptor Agonist, on Skin Inflammation in Mice

We investigated the effects of S-777469 (1-[[6-Ethyl-1-[4-fluorobenzyl]-5-methyl-2-oxo-1, 2-dihydropyridine-3-carbonyl]amino]-cyclohexanecarboxylic acid), a novel cannabinoid type 2 receptor (CB2) agonist, on 1-fluoro-2,4-dinitrobenzene (DNFB)-induced ear inflammation and mite antigen-induced dermatitis in mice. The oral administration of S-777469 significantly suppressed DNFB-induced ear swelling in a dose-dependent manner. In addition, S-777469 significantly alleviated mite antigen-induced atopic dermatitis-like skin lesions in NC/Nga mice. A histological analysis revealed that S-777469 significantly reduced the epidermal thickness and the number of mast cells infiltrating skin lesions. We demonstrated that S-777469 inhibited mite antigen-induced eosinophil accumulation in skin lesions and an endogenous CB2 ligand, 2-arachidonoylglycerol (2-AG)-induced eosinophil migration in vitro. Moreover, we confirmed that 2-AG levels significantly increased in skin lesions of mite antigen-induced dermatitis model. Together, these results suggest that S-777469 inhibits skin inflammation in mice by blocking the activities of 2-AG.

CHF6001 II: A Novel Phosphodiesterase 4 Inhibitor, Suitable for Topical Pulmonary Administration—In Vivo Preclinical Pharmacology Profile Defines a Potent Anti-Inflammatory Compound with a Wide Therapeutic Window

CHF6001 [(S)-3,5-dichloro-4-(2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2-(3-(cyclopropylmethoxy)-4-(methylsulfonamido)benzoyloxy)ethyl)pyridine 1-oxide] is a novel phosphodiesterase 4 (PDE4) inhibitor designed for use in pulmonary diseases by inhaled administration. Intratracheal administration of CHF6001 to ovalbumin-sensitized Brown-Norway rats suppressed the antigen-induced decline of lung functions (ED50 = 0.1 µmol/kg) and antigen-induced eosinophilia (ED50 = 0.03 µmol/kg) when administered (0.09 μmol/kg) up to 24 hours before antigen challenge, in agreement with CHF6001-sustained lung concentrations up to 72 hours after intratracheal treatment (mean residence time 26 hours). Intranasal, once daily administration of CHF6001 inhibited neutrophil infiltration observed after 11 days of tobacco smoke exposure in mice, both upon prophylactic (0.15-0.45 µmol/kg per day) or interventional (0.045-0.45 µmol/kg per day) treatment. CHF6001 was ineffective in reversing ketamine/xylazine-induced anesthesia (a surrogate of emesis in rat) up to 5 µmol/kg administered intratracheally, a dose 50- to 150-fold higher than anti-inflammatory ED50 observed in rats. When given topically to ferrets, no emesis and nausea were evident up to 10 to 20 µmol/kg, respectively, whereas the PDE4 inhibitor GSK-256066 (6-[3-(dimethylcarbamoyl)phenyl]sulfonyl-4-(3-methoxyanilino)-8-methylquinoline-3-carboxamide) induced nausea at 1 µmol/kg intratracheally. A 14-day inhalation toxicology study in rats showed a no-observed-adverse-effect level dose of 4.4 µmol/kg per day for CHF6001, lower than the 0.015 μmol/kg per day for GSK-256066. CHF6001 was found effective and extremely well tolerated upon topical administration in relevant animal models, and may represent a step forward in PDE4 inhibition for the treatment of asthma and chronic obstructive respiratory disease.

Proteinase-activated receptor 2 blockade impairs CCL11- or allergen-induced eosinophil recruitment in experimental pleurisy

Although proteinase-activated receptor (PAR)-2 has been implicated in inflammatory diseases, its role in regulating eosinophil recruitment in response to chemoattractants remains unclear. Here, we investigated the role of PAR-2 and PAR-2-activating Mast Cell (MC) tryptase on chemokine C–C motif ligand (CCL)11- and antigen-induced eosinophil recruitment to the pleural cavity of BALB/c mice. The PAR-2-activating peptide H–Ser–Leu–Ile–Gly–Arg–Leu–NH2 (SLIGRL–NH2) induced eosinophil recruitment whereas PAR-2 blockade inhibited ovalbumin (OVA)- or CCL11-induced eosinophil recruitment. Moreover, OVA and CCL11 induced PAR-2 expression in pleural leukocytes, and the MC tryptase inhibitor APC 366 ([N-(1-hydroxy-2-napthoyl)-l-arginyl-l-prolinamide hydrochloride]) abolished CCL11-induced eosinophil recruitment. These results suggest a pro inflammatory effect of PAR-2 and support a role for MC tryptase mediating eosinophil migration via PAR-2 signaling. Taken together, our results suggest that PAR-2 activation through endogenous MC tryptase activity could be required, at least partially, to mediate CCL11-induced eosinophil migration.

Existence of Antigen-Specific Immunoglobulin E Is Not Sufficient for Allergic Nasal Eosinophil Infiltration in Mice

Background: Immunoglobulin E (IgE) is important for the development of allergic rhinitis (AR), though the contribution of IgE to the infiltration of eosinophils in the nasal mucosa has not been fully elucidated. In this study, antigen-induced sneezing and nasal eosinophil accumulation were comparatively investigated in anti-ovalbumin (OVA)-IgE transgenic (Tg) and wild-type (WT) mice. Methods: Tg and OVA-immunized WT mice were intranasally challenged with OVA. Antigen-specific serum IgE level, sneezing and infiltration of eosinophil into the nasal cavity were then examined. Results: The level of serum OVA-specific IgE in Tg mice was significantly higher than that in antigen-immunized WT mice. Compared to saline challenge, intranasal challenge with OVA significantly induced sneezing in both Tg and immunized WT mice. However, antigen-induced nasal eosinophil infiltration was observed in immunized WT mice but not in Tg mice. Conclusions: IgE-mediated responses might not play a crucial role in antigen-induced eosinophil infiltration in AR.

IL-22 attenuates IL-25 production by lung epithelial cells and inhibits antigen-induced eosinophilic airway inflammation

IL-22 functions as both a proinflammatory cytokine and an anti-inflammatory cytokine in various inflammations, depending on the cellular and cytokine milieu. However, the roles of IL-22 in the regulation of allergic airway inflammation are still largely unknown. We sought to determine whether IL-22 is involved in the regulation of allergic airway inflammation. We examined IL-22 production and its cellular source at the site of antigen-induced airway inflammation in mice. We also examined the effect of IL-22 neutralization, as well as IL-22 administration, on antigen-induced airway inflammation. We finally examined the effect of IL-22 on IL-25 production from a lung epithelial cell line (MLE-15 cells). Antigen inhalation induced IL-22 production in the airways of sensitized mice. CD4(+) T cells, but not other lymphocytes or innate cells, infiltrating in the airways produced IL-22, and one third of IL-22-producing CD4(+) T cells also produced IL-17A. The neutralization of IL-22 by anti-IL-22 antibody enhanced antigen-induced IL-13 production, eosinophil recruitment, and goblet cell hyperplasia in the airways. On the other hand, intranasal administration of recombinant IL-22 attenuated antigen-induced eosinophil recruitment into the airways. Moreover, anti-IL-22 antibody enhanced antigen-induced IL-25 production in the airways, and anti-IL-25 antibody reversed the enhancing effect of anti-IL-22 antibody on antigen-induced eosinophil recruitment into the airways. Finally, IL-22 inhibited IL-13-mediated enhancement of IL-25 expression in IL-1β- or LPS-stimulated MLE-15 cells. IL-22 attenuates antigen-induced airway inflammation, possibly by inhibiting IL-25 production by lung epithelial cells.

GGTI-2133, an Inhibitor of Geranylgeranyltransferase, Inhibits Infiltration of Inflammatory Cells into Airways in Mouse Experimental Asthma

Statins have been proposed as a novel treatment of respiratory diseases including asthma. Although the mechanism of anti-inflammatory effect of statins is still unclear, an inhibition of protein prenylation by depleting the downstream metabolites of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase might be involved. To test the hypothesis, the effects of GGTI-2133, a direct inhibitor of geran ylgeranyltransferase (GGTase), on antigen-induced airway inflammation were investigated in a murine model of allergic bronchial asthma. Mice were sensitized and repeatedly challenged with ovalbumin antigen (OA). Animals were also treated with GGTI-2133 (5 mg/kg/day, i.p.) once a day before and during the antigen inhalation period. Repeated antigen inhalation caused an infiltration of inflammatory cells, especially eosinophils, into airways. Significant increases in interleukin (IL)-4, IL-13, eotaxin, thymus and activation-regulated chemokine (TARC) and leukotriene B4 (LTB4) in bronchoalveolar lavage fluids and total and OA-specific IgE in sera were also found in the antigen-exposed animals. The systemic treatments with GGTI-2133 inhibited the antigen-induced eosinophil infiltration into airways almost completely. However, interestingly, the GGTI-2133 treatment did not affect the levels of these chemotactic factors and IgE. These findings suggest that selective inhibition of GGTase is effective for eosinophilic airway inflammation such as asthma.

Prostaglandin E2 Receptor EP2, EP3, and EP4 Agonists Inhibit Antigen-Induced Mucus Hypersecretion in the Nasal Epithelium of Sensitized Rats

Prostaglandin (PG) E2 is a potential anti-inflammatory mediator that attenuates airway inflammation. To elucidate the functions of the PGE2 receptors (EP1, EP2, EP3, and EP4) in allergic inflammation, we examined the in vivo effects of EP agonists on mucus hypersecretion and eosinophil infiltration in rat nasal epithelium. We induced hypertrophic and metaplastic changes in goblet cells in nasal epithelium of ovalbumin-sensitized rats by intranasal challenge with ovalbumin. The effects of subcutaneous injections of EP agonists on mucus production and eosinophil infiltration were examined. The EP4 agonist (1 to 100 microg/kg) dose-dependently inhibited ovalbumin-induced mucus production. The EP2 and EP3 agonists (100 microg/kg) also significantly inhibited mucus production. The EP3 agonist inhibited antigen-induced eosinophil infiltration, whereas the EP1 agonist showed no effect. This suppression of mucus production by the EP4 agonist was only effective when the EP4 agonist was given in the effector phase; administration in the induction phase resulted in no effect. These results indicate that PGE2 acts as an anti-inflammatory mediator via the EP receptors of airways in allergic inflammation. Selective EP agonists may provide a new therapeutic strategy for airway mucus hypersecretion.

IL-23 and Th17 Cells Enhance Th2-Cell–mediated Eosinophilic Airway Inflammation in Mice

The IL-23-IL-17A-producing CD4(+) T-cell (Th17 cell) axis plays an important role in the development of chronic inflammatory diseases, including autoimmune diseases. However, the role of the IL-23-Th17 cell axis in the regulation of allergic airway inflammation is still largely unknown. To determine the role of IL-23 and Th17 cells in allergic airway inflammation. We examined the effect of anti-IL-23 antibody on antigen-induced airway inflammation. We also investigated the effect of enforced expression of IL-23 on allergic airway inflammation by generating lung-specific IL-23 transgenic mice. Moreover, we examined the effect of adoptive transfer of antigen-specific Th17 cells on allergic airway inflammation. IL-23 mRNA was expressed in the lung of sensitized mice upon antigen inhalation, and the neutralization of IL-23 decreased antigen-induced eosinophil recruitment and Th2 cytokine production in the airways. The enforced expression of IL-23 in the airways significantly enhanced antigen-induced eosinophil and neutrophil recruitment into the airways; Th2 cytokine, IL-17A, and tumor necrosis factor (TNF)-alpha production in the airways; goblet cell hyperplasia; and airway hyperresponsiveness. Moreover, IL-23-mediated enhancement of antigen-induced Th2 cytokine production and eosinophil recruitment in the airways was still observed in the mice lacking IL-17A. Furthermore, although adoptive transfer of antigen-specific Th17 cells alone induced neutrophil but not eosinophil recruitment into the airways upon antigen inhalation, cotransfer of Th17 cells with Th2 cells significantly enhanced antigen-induced Th2-cell-mediated eosinophil recruitment into the airways and airway hyperresponsiveness. IL-23 and Th17 cells not only induce Th17-cell-mediated neutrophilic airway inflammation but also up-regulate Th2-cell-mediated eosinophilic airway inflammation.

GS143, an IκB ubiquitination inhibitor, inhibits allergic airway inflammation in mice

Asthma is characterized by airway inflammation with intense eosinophil infiltration and mucus hyper-production, in which antigen-specific Th2 cells play critical roles. Nuclear factor-κB (NF-κB) pathway has been demonstrated to be essential for the production of Th2 cytokines and chemokines in the airways in murine asthma models. In the present study, we examined the effect of GS143, a novel small-molecule inhibitor of IκB ubiquitination, on antigen-induced airway inflammation and Th2 cytokine production in mice. Intranasal administration of GS143 prior to antigen challenge suppressed antigen-induced NF-κB activation in the lung of sensitized mice. Intranasal administration of GS143 also inhibited antigen-induced eosinophil and lymphocyte recruitment into the airways as well as the expression of Th2 cytokines and eotaxin in the airways. Moreover, GS143 inhibited antigen-induced differentiation of Th2 cells but not of Th1 cells in vitro. Taken together, these results suggest that IκB ubiquitination inhibitor may have therapeutic potential against asthma.

Dietary Phytoestrogens Have Anti-Inflammatory Activity in a Guinea Pig Model of Asthma

Abstract. Phytoestrogens are a normal constituent of soy protein and have been shown to have anti-inflammatory activity in various in vitro and in vivo models. The present study was designed to determine if a diet enriched in the phytoestrogen isoflavones, genistin and daidzin, would alter the antigen-induced cellular infiltration, particularly eosinophilia, characteristic of a guinea pig model of asthma. Throughout the duration of the study, guinea pigs were maintained on a control diet (standard guinea pig chow) or the same diet enriched in isoflavones. The animals were placed on the diet 2 weeks prior to active sensitization with ovalbumin (OA). Three weeks after sensitization, animals were challenged with OA aerosol. The cellular infiltration into the lung and protein and red blood cells (RBC) in the bronchoalveolar lavage fluid (BAL) were determined 17 hr later. In animals maintained on the control diet, OA aerosol challenge resulted in the expected increase in eosinophils in both the BAL and the lung tissue, an increase in neutrophils in the BAL, and an increase in protein and the number of RBC in the BAL. In contrast, in animals maintained on the isoflavone diet, the OA-induced eosinophilia in the lung tissue was significantly attenuated. In addition, OA challenge caused a greater increase in BAL protein in animals maintained on the isoflavone diet compared with animals on the control diet. Our results indicated that a diet enriched in isoflavones results in reduced antigen-induced eosinophilia in the lung in the guinea pig model of asthma. However, this beneficial anti-inflammatory effect of dietary phytoestrogens is accompanied by a potentially detrimental increase in antigen-induced leakage of protein into the airspace.

B and T Lymphocyte Attenuator Inhibits Antigen-Induced Eosinophil Recruitment into the Airways

Background: Signaling through CD28 family co-receptors regulates activation of CD4⁺ T cells positively and negatively. It has been shown that stimulatory co-receptors such as CD28 and ICOS play critical roles in the induction of allergic airway inflammation. However, the role of B and T lymphocyte attenuator (BTLA), an inhibitory co-receptor expressed preferentially in Th1 cells, in the regulation of allergic airway inflammation remains to be determined. Methods: We examined antigen-induced eosinophil recruitment and cytokine production in the airways in antigen-sensitized BTLA-deficient (BTLA–/–) mice. We also examined antigen-induced cytokine production and cell proliferation of splenic T cells in antigen-sensitized BTLA–/– mice. Results: Antigen-induced eosinophil recruitment and IL-5 production in the airways was enhanced in antigen-sensitized BTLA–/– mice. On the other hand, antigen-induced Th1 and Th2 cytokine production as well as T cell proliferation of splenocytes was normal in BTLA–/–mice. Conclusion: BTLA inhibits antigen-induced eosinophil recruitment into the airways by preventing IL-5 production from Th2 cells.

Effect of tecastemizole on pulmonary and cutaneous allergic inflammatory responses

Tecastemizole, a major metabolite of astemizole, is a potent and selective H1 receptor antagonist. Evidence suggests that this and certain other H1 receptor antagonists may possess anti-inflammatory effects that are, in some cases, independent of H1 receptor antagonism. Objective The aim of this study was to investigate the anti-inflammatory effects of tectastemizole in models of allergic inflammation. Effects of tecastemizole were assessed in a murine model of allergic lung inflammation, in passive cutaneous anaphylaxis (PCA) responses in guinea-pig skin and in in vitro assays measuring endothelial adhesion molecule expression and leucocyte-endothelial adhesion. Tecastemizole inhibited antigen-induced eosinophil recruitment to the lungs of allergic mice in a dose-dependent manner. Furthermore, combination of a sub-effective dose of tecastemizole, combined with a sub-effective dose of dexamethasone inhibited eosinophil accumulation in this model. Plasma extravasation in PCA reactions was inhibited by tecastemizole, although by a mechanism that would appear to be H1 receptor-dependent. Cytokine-induced endothelial intercellular adhesion molecule-1 and vascular cell adhesion molecule-1 expression, as well as mononuclear cell adhesion to human umbilical vein endothelial cells was inhibited by tecastemazole in a manner independent of H1 receptor antagonism. These data suggest that tecastemizole may have H1 receptor-independent effects in inhibiting late-phase inflammatory responses, while acute responses appear to be inhibited in a H1 receptor-dependent manner. Furthermore, our data suggest an important potential steroid-sparing role for such drugs in the treatment of allergic inflammatory conditions.

T-bet inhibits both T H2 cell–mediated eosinophil recruitment and T H17 cell–mediated neutrophil recruitment into the airways

Previous studies have shown that mice lacking T-bet, a critical transcription factor for T(H)1 cell differentiation, spontaneously develop airway inflammation with intense eosinophil infiltrates. However, the mechanism underlying T-bet-mediated inhibition of allergic airway inflammation is still unknown. To determine the regulatory role of T-bet in antigen-induced allergic airway inflammation. We examined the role of T-bet in antigen-induced allergic airway inflammation using T-bet(-/-) mice on a BALB/c background that did not develop spontaneous airway inflammation. We also examined the role of T-bet expression of CD4(+) T cells in airway inflammation by adoptive transfer experiments. We found that antigen-induced eosinophil recruitment, goblet cell hyperplasia, and T(H)2 cytokine production in the airways were enhanced in T-bet(-/-) mice. However, in the absence of signal transducer and activator of transcription 6 (STAT6), T-bet deficiency could not induce the antigen-induced eosinophilic airway inflammation. Adoptive transfer of T-bet(-/-) or T-bet(+/+) CD4(+) T cells to T-bet(-/-)Rag-2(-/-) mice revealed that the expression of T-bet in CD4(+) T cells was vital for the inhibition of antigen-induced eosinophilic airway inflammation. Interestingly, antigen-induced neutrophil recruitment in the airways was also enhanced in T-bet(-/-) mice. Moreover, T-bet(-/-) CD4(+) T cells preferentially differentiated into IL-17-producing cells that mediated neutrophilic airway inflammation. T-bet inhibits both T(H)2 cell-mediated eosinophilic inflammation and T(H)17 cell-mediated neutrophilic inflammation in the airways. The dysfunction of T-bet may be involved in the pathogenesis of severe asthma, in which accumulation of neutrophils as well as eosinophils in the airways is a hallmark of disease.

YM-58483, a selective CRAC channel inhibitor, prevents antigen-induced airway eosinophilia and late phase asthmatic responses via Th2 cytokine inhibition in animal models

T cells play a regulatory role in the pathogenesis of various immune and allergic diseases, including human asthma. Recently, it was reported that a pyrazole derivative, YM-58483 (BTP2), potently inhibits Ca 2+ release-activated Ca 2+ (CRAC) channels and interleukin (IL)-2 production in T cells. We investigated the effects of YM-58483 on T helper type 2 (Th2) cytokine production in vitro and antigen-induced airway asthmatic responses in vivo. YM-58483 inhibited IL-4 and IL-5 production in a conalbumine-stimulated murine Th2 T cell clone (D10.G4.1), and IL-5 production in phytohemagglutinin-stimulated human whole blood cells with IC 50 values comparable to those reported for its CRAC channel inhibition (around 100 nM). YM-58483 inhibited antigen-induced eosinophil infiltration into airways, and decreased IL-4 and cysteinyl-leukotrienes content in inflammatory airways induced in actively sensitized Brown Norway rats. Furthermore, orally administered YM-58483 prevented antigen-induced late phase asthmatic broncoconstriction and eosinophil infiltration in actively sensitized guinea pigs. These data suggest that the inhibition of Ca 2+ influx through CRAC channel leads to the prevention of antigen-induced airway inflammation, probably via the inhibition of Th2 cytokine production and inflammatory mediators release. YM-58483 may therefore be useful for treating airway inflammation in bronchial asthma.

IL-25 enhances allergic airway inflammation by amplifying a T H2 cell–dependent pathway in mice

A novel IL-17 family cytokine, IL-25, has been reported to induce IL-4, IL-5, and IL-13 production from undefined non-T/non-B cells and then induce T(H)2-type immune responses. However, the roles of IL-25 in inducing allergic airway inflammation remain unknown. We sought to determine whether IL-25 is involved in causing allergic airway inflammation. We examined the expression of IL-25 mRNA in the lungs of sensitized mice on antigen inhalation. We also examined the effect of IL-25 neutralization by soluble IL-25 receptor on antigen-induced airway inflammation. We then generated IL-25 transgenic mice that express IL-25 specifically in the lung under the control of the Clara cells-10-kd protein promoter and investigated the effect of enforced IL-25 expression on antigen-induced airway inflammation. IL-25 mRNA was expressed in the lungs of sensitized mice on antigen inhalation, and the neutralization of IL-25 by soluble IL-25 receptor decreased antigen-induced eosinophil and CD4(+) T-cell recruitment into the airways. The enforced expression of IL-25 in the lung itself failed to induce allergic airway inflammation, whereas the expression of IL-25 significantly enhanced antigen-induced T(H)2 cytokine production, eosinophil and CD4(+) T cell recruitment, and goblet cell hyperplasia in the airways. Moreover, IL-25-induced enhancement of allergic airway inflammation was inhibited by the depletion of CD4(+) T cells or by the absence of signal transducer and activator of transcription 6. IL-25 enhances antigen-induced allergic airway inflammation by amplifying a T(H)2 cell-dependent pathway. IL-25 might be involved in the enhancement, prolongation, or both of T(H)2 cell-mediated allergic diseases, such as asthma.

Interleukin 25 in Allergic Airway Inflammation

T helper 2 (Th2) cells induce allergic inflammation through the production of cytokines such as interleukin (IL)-4, IL-5 and IL-13. Recently, it has been demonstrated that a novel IL-17 family cytokine IL-25 (IL-17E) is a product of activated Th2 cells and mast cells. Interestingly, when systemically administered to mice, IL-25 induces IL-4, IL-5 and IL-13 production from undefined non-T/non-B cells and then induces Th2-type immune responses such as blood eosinophilia and increased serum immunoglobulin E levels. In addition, we have recently shown that IL-25 mRNA is expressed in the lung after an inhaled antigen challenge in sensitized mice and that neutralization of the produced IL-25 by soluble IL-25 receptor decreases antigen-induced eosinophil and CD4+ T cell recruitment into the airways. Moreover, we have shown that the enforced expression of IL-25 in the lung significantly enhances antigen-induced Th2 cytokine production and eosinophil recruitment into the airways, and that the IL-25-mediated enhancement of antigen-induced eosinophil recruitment is inhibited by the depletion of CD4+ T cells. Thus, it is suggested that IL-25 plays an important role in enhancing allergic airway inflammation by a CD4+ T-cell-dependent mechanism.

Quantitative expression levels of regulated on activation, normal T cell expressed and secreted and eotaxin transcripts in toluene diisocyanate-induced allergic rats

ConclusionThese results suggest that eotaxin may play a predominant role in controlling antigen-induced eosinophil recruitment into tissue.ObjectiveTo investigate the expression levels of regulated on activation, normal T cell expressed and secreted (RANTES) mRNA and eotaxin mRNA in the nasal mucosa of toluene diisocyanate (TDI)-induced allergic rats and to evaluate which of them is primarily related to selective eosinophilic infiltration by comparing their expression levels with the numbers of infiltrated eosinophils and vascular cell adhesion molecule-1 (VCAM-1).Material and methodsWe quantified the expression levels of two strong eosinophilic CC chemokines (RANTES and eotaxin) and VCAM-1 at mRNA levels in the nasal mucosa of TDI-induced allergic rats using competitive polymerase chain reaction and compared their expression levels with the number of infiltrated eosinophils.ResultsThe number of infiltrated eosinophils was significantly increased between 3 h and Day 4 in TDI-induced allergic rats, but had decreased by Day 5. VCAM-1 mRNA expression was also increased between 3 h and Day 4. The number of infiltrated eosinophils correlated with the expression levels of VCAM-1 mRNA (p<0.01). In contrast, expression of RANTES mRNA and eotaxin mRNA was increased between 3 h and Day 2, peaked between Days 1 and 2 and then declined. Although the expression of both chemokines correlated with the numbers of infiltrated eosinophils (p<0.01), peak expression levels of eotaxin mRNA were 14-fold higher than baseline levels whereas RANTES mRNA expression increased 3-fold.

Effect of a novel interleukin-5 receptor antagonist, YM-90709, on antigen-induced eosinophil infiltration into the airway of BDF1 mice

A newly synthesized compound, YM-90709, 2,3-dimethoxy-6,6-dimethyl-5,6-dihydrobenzo[7,8]indolizino[2,3- b]quinoxaline, was previously reported to specifically inhibit the binding of interleukin-5 (IL-5) to its receptor (R) on human eosinophils. In this study, the intravenous injection of YM-90709 inhibited antigen-induced infiltration of eosinophils into the bronchoalveolar lavage fluid (BALF) of BDF1 mice, with an ED 50 value of 0.050 mg/kg. Anti-murine IL-5 monoclonal antibody (mAb) also inhibited the infiltration of eosinophils with an ED 50 value of 0.035 mg/kg. These results indicate that YM-90709, which is a novel IL-5R antagonist, inhibits antigen-induced eosinophil recruitment into the airway, the same as anti-IL-5 mAb does.

Lung eosinophilic inflammation and airway hyperreactivity are enhanced by murine anaphylactic, but not nonanaphylactic, IgG1 antibodies

BackgroundChronic airway inflammation is a fundamental feature of bronchial asthma, which is characterized by the accumulation and activation of inflammatory cells, such as mast cells and eosinophils, that are tightly regulated by TH2 cytokines and chemokines. Recently, we demonstrated, in a murine model of asthma with immunosuppressed mice reconstituted with antigen-specific IgE or IgG1 antibodies, that IgE, but not IgG1, participates in potentiation of airway inflammation and induction of airway hyperreactivity (AHR). The IgG1 antibody, however, did not elicit passive cutaneous anaphylactic reactions, which was in contrast to IgE. ObjectivesBecause 2 types of murine IgG1 have been demonstrated with regard to anaphylactic activity, the present experiments were undertaken to determine the role of anaphylactic and nonanaphylactic IgG1 antibodies in the development of antigen-induced eosinophilia and AHR in this model. MethodsDinitrophenyl-conjugated, heat-coagulated hen's egg white was implanted in immunosuppressed mice reconstituted with anaphylactic or nonanaphylactic IgG1. Intratracheal challenge with aggregated dinitrophenyl-ovalbumin was performed on day 14, and lung inflammatory and mechanical parameters were evaluated after 48 hours. ResultsOur results demonstrated that reconstitution of immunosuppressed mice with anaphylactic IgG1 antibodies in contrast to nonanaphylactic IgG1 antibodies potentiates their ability to have pulmonary eosinophilic inflammation and AHR. IL-5 and eotaxin levels in bronchoalveolar lavage fluid from anaphylactic IgG1-reconstituted mice were also higher than those in nonanaphylactic IgG1-reconstituted mice. ConclusionsThese results indicate that the anaphylactic property of murine IgG1 molecules is essential for their capacity to enhance lung eosinophilic inflammation and to induce AHR.