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Background: There is growing interest in probiotics such as lactic acid bacteria (LAB), not only for treatment of T helper type (Th) 1-mediated diseases but also for Th2-mediated diseases, including allergic diseases, since lactic acid bacteria may be able to modulate the Th1/Th2 balance, in addition to having an immunomodulative effect through induction of Th1 bias., Methods: The effect of oral administration of heat-killed Lactobacillus acidophilus Strain L-92 (L-92) on ovalbumin (OVA)-specific immunoglobulin (Ig)E production was investigated in BALB/c mice. L-92 was orally administered to mice for 8 weeks from 2 weeks after initiation of OVA-immunization. Patterns of cytokine and Ig production in splenocytes and cells from Peyer's patches (PPs) from these mice were examined after restimulation with OVA in vitro., Results: L-92 significantly suppressed serum OVA-specific IgE levels for a long period. Cytokines such as interferon (IFN)-gamma, interleukin (IL)-4 and IL-10 and Igs such as total IgE and OVA-specific IgE were produced at significantly lower levels by splenocytes of L-92-treated mice, compared with those of control mice. In contrast, transforming growth factor (TGF)-beta and IgA levels produced by PPs from L-92-treated mice were significantly higher than in those from control mice., Conclusions: Oral L-92 administration regulated both Th1 and Th2 cytokine responses, suppressed serum OVA-specific IgE, and induced TGF-beta production in PPs. TGF-beta is known to be associated with activation of regulatory T (Treg) cells. These data suggest that LAB may have immunomodulative effect by Treg cells via TGF-beta activity.

In the present study, we examined the inhibitory effects of the beta2-adrenoceptor agonists isoproterenol, salbutamol, fenoterol, and clenbuterol, on the release of chemical mediators from cultured human mast cells after prolonged treatment with the agonists. Although preincubation of sensitized mast cells for 10 min with beta2-adrenoceptor agonists potently inhibited mediator release, prolongation of the preincubation period up to 240 min attenuated the inhibition. The attenuation of histamine release inhibition was potent when compared with that of prostaglandin D2 (PGD2) and cysteinyl leukotriene (LT) release inhibition. In contrast, forskolin inhibited mediator release and the inhibition increased gradually in proportion to the preincubation period. The reduced inhibition by the beta2-adrenoceptor agonists was compensated for by simultaneous treatment with cholera toxin. The beta2-adrenoceptor agonists elevated intracellular cAMP levels after 10-min incubation and the elevated levels were almost comparable to those after 240-min incubation. Forskolin elevated the intracellular cAMP levels more potently after incubation for 240 min than after 10 min. When mast cells were incubated for 3 d with the beta2-adrenoceptor agonists, similar attenuation of mediator release inhibition was observed. Elevation of intracellular cAMP levels was also attenuated, although beta2-adrenoceptor mRNA expression was potentiated. The present results collectively indicate that the attenuation of mediator release inhibition by beta2-adrenoceptor agonists under the present experimental conditions involves uncoupling between beta2-adrenoceptors and Gs proteins. Furthermore, the beta2-adrenoceptor desensitization causes differential attenuating effects on the inhibition of histamine, PGD2, and LT release, suggesting that downstream events involved in each inhibitory pathway have different sensitivity to receptor desensitization.

Btk plays crucial roles in the differentiation and activation of B and myeloid cells. Despite drastic reductions of other Ig isotypes, paradoxically high IgE responses have been known in btk mutant mice. Here we show that btk-/- dendritic cells exhibit a more mature phenotype and a stronger in vitro and in vivo T cell- stimulatory ability than wild-type cells. Increased IgE responses were induced by adoptive transfer of btk-/- dendritic cells into mice. Consistent with the stronger T cell-stimulatory ability of btk-/- dendritic cells, btk-/- mice exhibited enhanced inflammation in Th2-driven asthma and Th1-driven contact sensitivity experiments. These negative regulatory functions of Btk in dendritic cells appear to be mediated mainly through autocrine secretion of IL-10 and subsequent activation of Stat3. [ABSTRACT FROM AUTHOR]

Background: The role of 5-lipoxygenase (5-LO) products in the asthmatic bronchoconstriction is evident. However, the role of 5-LO products in airway hyperresponsiveness (AHR) and airway inflammation is still under discussion. The aim of the present study is to investigate the role of leukotriene D[sub 4] (LTD[sub 4] ) in AHR and allergic airway eosinophilia in mice. Methods: The effect of LTD[sub 4] inhalation on antigen-induced AHR and airway eosinophilia was investigated in 5-LO gene-deficient mice. Results: After three inhalations of LTD[sub 4] , airway responsiveness to acetylcholine was not altered in normal or allergic wild-type and 5-LO knockout (KO) mice. In contrast, the number of eosinophils in 5-LO KO allergic mice increased to the level of wild-type allergic mice after the inhalation of LTD[sub 4] . These observations were confirmed by a histopathological study of the lungs. No change in the cytokine levels in bronchoalveolar lavage fluid and serum immunoglobulin levels was shown after LTD[sub 4] inhalation. Conclusion: These findings suggest that LTD[sub 4] plays a role in eosinophilic airway inflammation but not in AHR in mice.Copyright © 2002 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Background: Itching in humans is attenuated by μ-opioid receptor antagonists. ICR mice display increases in scratching behavior upon induction of IgE-mediated passive cutaneous anaphylaxis (PCA), or intradermal injection of compound 48/80 or histamine. Methods: Cutaneous reactions were induced in ICR mice by IgE-mediated PCA, compound 48/80 and histamine, and the scratching behavior associated with the cutaneous reactions was evaluated. Results: Naloxone and nalmefene reduced the incidence of scratching behavior associated with PCA. Naloxone also inhibited the induction of scratching behavior caused by compound 48/80 and histamine. Naloxone did not affect the increase in vascular permeability caused by PCA and injection of compound 48/80. Conclusion: Scratching behavior in mice may be induced by a sensation or a mechanism similar to itching in humans and should become a useful model for examining itching in humans.Copyright © 2000 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

The role of nitric oxide (NO) in the development of allergic cutaneous reactions in mice was investigated. A biphasic cutaneous reaction composed of an immediate-phase edema and a late-phase edema was evoked by epicutaneous application of 2,4-dinitrofluorobenzene on the ear of mice passively sensitized with mouse anti-dinitrophenol monoclonal IgE. Two NO synthase inhibitors, L-N[sup G] -nitroarginine methyl ester (L-NAME) and N[sup G] -monomethyl-L-arginine, significantly inhibited both phases of the IgE-mediated biphasic cutaneous reaction. Simultaneous treatment with L-arginine attenuated the inhibitory effect of L-NAME. An NO donor, 3-morpholinosydononimine-N-ethylcarbamide, caused a potent edematous reaction in the mouse ear. Furthermore, L-NAME inhibited the cutaneous reactions caused by both interleukin-1β and tumor necrosis factor-α, putative mediators of the late-phase edema in the biphasic cutaneous reaction. These results indicate that a gaseous mediator, NO, participates, at least in part, in the development of ear edema in the IgE-mediated biphasic cutaneous reaction in mice. [ABSTRACT FROM AUTHOR]

Investigates the role of immunoglobulin E for the onset of eczematous dermatitis. Materials and methods; Data on ear thickness, serum immunoglobulin levels and the expression of cytokine and productive Cε messenger RNA.

Abstract: Itching is the most important problem in atopic dermatitis and tacrolimus has been suggested to attenuate the itching by topical application. However, the anti-itch mechanism of tacrolimus has not been well elucidated. In the present study, an allergic dermatitis accompanied by frequent scratching behaviors was induced by repeated paintings with 2,4-dinitrofluorobenzene (DNFB) acetone solution onto the mouse ear and the effects of tacrolimus and dexamethasone on the dermatitis and associated scratching behavior were comparatively examined. Repeated DNFB paintings caused a typical dermatitis accompanied by elevated serum immunoglobulin E (IgE) and frequent scratching behaviors. Both tacrolimus and dexamethasone given topically for 10days before the final challenge significantly inhibited the ear swelling and reduced the expression of interferon-γ mRNA. Dexamethasone inhibited the accumulation of eosinophils completely, although tacrolimus did not. Both drugs did not affect the elevation of serum IgE levels. Tacrolimus significantly inhibited the scratching behavior, whereas dexamethasone failed to affect it. Repeated DNFB challenge depleted substance P in the dermis. Treatment with tacrolimus before the final challenge completely inhibited the recovery of substance P content, whereas dexamethasone facilitated the recovery. DNFB-induced ear swelling and scratching behavior were significantly inhibited by FK888, a tachykinin NK1 receptor antagonist. Therefore, substance P seems to participate in the induction of ear swelling and scratching behavior upon final challenge with DNFB, and depletion of substance P by tacrolimus in the dermis contributes to its inhibition of ear swelling and scratching behavior at least in part. [Copyright &y& Elsevier]

Abstract: In previous report, we have shown that trichloroethylene (TCE) increases histamine release and inflammatory cytokine production from antigen-stimulated mast cells. In this study, we examined the enhancing effect of a small amount of TCE ingestion from drinking water on antigen-stimulated allergic responses. After exposure of Wistar rats to TCE ingestion for 2 or 4 weeks, we performed a passive cutaneous anaphylaxis (PCA) reaction. TCE ingestion for 2 and 4 weeks enhanced PCA reaction in a dose-dependent manner. On histological examination, TCE ingestion for 2 weeks exacerbated inflammation characterized by infiltration of lymphocytes and accumulation of mast cells around the vessel in the skin. After TCE ingestion for 4 weeks, the mesenteric lymph nodes (MLNs) showed increase of the size and wet weight, and germinal centers changed distinctly. The interleukin-4 (IL-4) mRNA levels on spleen, MLNs and leukocytes were increased. Moreover, serum total IgE levels of TCE ingestion increased in a time-dependent manner. Our results suggest that TCE ingestion induces pro-inflammatory responses and causes Th1/Th2-type helper T-cell imbalance. And more, a small amount of TCE ingestion may lead to the initiation and acceleration of type I allergic reaction. [Copyright &y& Elsevier]

Background: The clinical efficacy of combination therapy comprising a long acting β2-agonist (LABA) and corticosteroid is widely recognized for the treatment of adult asthma. Here we examine the effect of salmeterol xinafoate (SX) and fluticasone propionate (FP) alone and in combination on the immunological activation of human cultured mast cells (HCMC) in vitro. Methods: HCMC were passively sensitized with IgE antibody and then activated by challenging with anti-IgE antibody. The effect of drugs on the activation of mast cells was examined by measuring the amount of released chemical mediators (histamine, leukotrienes (LT) and prostaglandin D2 (PGD2 )) and granulocyte macrophage colony stimulating factor (GM-CSF). Results: The release of each chemical mediator was inhibited by 10-9-10-8M SX but not by 10-10-10-7M FP. The production of GM-CSF was inhibited by a concentration of 10-8M in both drugs and the inhibition was augmented by combined treatment with 10-11M of each drug. Conclusions: The immunological release of chemical mediators (histamine, LT, PGD2) from HCMC was inhibited by SX but not by FP. SX and FP inhibited the production of GM-CSF by HCMC and both drug showed synergistic inhibition in the production of GM-CSF. [ABSTRACT FROM AUTHOR]

Abstract: Itching is the most important problem in many allergic and inflammatory skin diseases especially in atopic dermatitis. However, animal models for allergic dermatitis useful for the study of itching have rarely been established. We established a mouse allergic dermatitis model involving frequent scratching behavior by repeated painting with 2,4-dinitrofluorobenzene (DNFB) acetone solution onto the mouse skin, and comparatively examined the effects of tacrolimus and dexamethasone on the dermatitis and associated scratching behavior. Repeated DNFB painting caused typical dermatitis accompanied by elevated serum immunoglobulin E (IgE) and frequent scratching behavior. An apparent thickening of the epidermis and dermis, and the significant accumulation of inflammatory cells were observed. Increased interferon (IFN)-γ mRNA expression and the induction of interleukin (IL)-4 and IL-5 mRNA expression were also observed in the skin lesion. The scratching behavior was inhibited by dibucaine and naloxone. Although tacrolimus reduced the increased expression of IFN-γ and IL-4 mRNA, dexamethasone potently depressed that of IFN-γ, IL-4 and IL-5 mRNA. Dexamethasone inhibited the accumulation of lymphocytes and eosinophils, although tacrolimus did not. Both drugs failed to inhibit the elevation of serum IgE levels. Tacrolimus significantly inhibited the scratching behavior that was associated with the inhibition of nerve fiber extension into the epidermis, whereas dexamethasone failed to have any effect. The mouse dermatitis model seems to be beneficial for the study of itching associated with allergic dermatitis, such as atopic dermatitis, and tacrolimus seems to exhibit an anti-itch effect through the inhibition of nerve fiber extension at least in part. [Copyright &y& Elsevier]

ABSTRACT Background: In the present study, we investigated the effect of social isolation stress on IgE-mediated triphasic cutaneous reactions after 2,4-dinitrofluorobenzene (DNFB) challenge in male BALB/c mice passively sensitized with anti-dinitrophenol (DNP) IgE antibody, and examined the effects of Yokukan-san (a Kampo medicine with antipsychotic action) and a reference drug (diazepam) on the stress-enhanced cutaneous reaction. Methods/Results: In response to challenge with 0.01, 0.025 and 0.05% DNFB, triphasic skin reactions, including an immediate-phase response (IPR), a late-phase response (LPR) and a very late-phase response (vLPR) at 1 and 24 h and 8 days after antigen challenge, respectively, were increased in socially isolated mice compared with group-housed mice. Oral administration of Yokukan-san attenuated the isolation stress-exacerbated triphasic skin reactions in a dose-dependent manner, whereas it had no significant effect on cutaneous reactions in the unstressed group-housed mice. In contrast, intraperitoneal administration of diazepam, a classic benzodiazepine receptor agonist, suppressed the enhanced IPR and LPR in socially isolated mice but, surprisingly, stimulated vLPR in both stressed and unstressed mice, showing different efficacy to Yokukan-san. Moreover, the elevated locomotor activity in socially isolated mice was reduced by Yokukan-san and diazepam, while the isolation stress-induced aggressive behavior was normalized only by diazepam and not by Yokukan-san. Conclusions: The results of the present study indicate that IgE-mediated triphasic cutaneous reactions were exacerbated by social isolation stress and suggest that Yokukan-san and diazepam antagonize isolation stress-induced cutaneous reactions partly through their sedative action on social isolation stress. [ABSTRACT FROM AUTHOR]