Roles for IL-1 and TNFalpha in dynamic behavioral responses of Langerhans cells to topical hapten application.

BACKGROUND: To understand the behavioral biology of Langerhans cells (LCs), we recently recorded time-lapse images of LCs in the knock-in mice expressing the I-Abeta chain tagged with the enhanced green fluorescence protein (EGFP). EGFP(+) LCs showed relatively limited motility in the steady state, whereas topical application of dinitrofluorobenzene (DNFB) markedly augmented a unique movement of dendrites characterized by rhythmic extension and retraction, termed dSEARCH, and triggered amoeba-like lateral migration of cell bodies. OBJECTIVE: To define underlying mechanisms by which hapten treatment alters LC behaviors. METHODS: The I-Abeta-EGFP mice received subcutaneous (s.c.) injection of recombinant IL-1alpha or TNFalpha (50 ng/animal) and dynamic behaviors of EGFP(+) LCs were recorded by time-lapse confocal microscopy at several time points to measure their dSEARCH activities and lateral migration. In a different set of experiments, IL-1 receptor antagonist (IL-1Ra) or soluble TNF receptor-2 (sTNFR2) (0.5 microg/animal) was s.c. injected into the ear skin 30 min before topical application of DNFB, and LC behaviors analyzed 30 h later. RESULTS: Local injection of IL-1alpha or TNFalpha induced significant, albeit modest, augmentation of both dSEARCH and lateral migration. Co-injection of TNFalpha and IL-1alpha further exacerbated motile activities in a synergistic manner by similar magnitudes observed after DNFB application. Conversely, DNFB-induced behavioral changes were inhibited completely by local injection of IL-1Ra or sTNFR2. CONCLUSION: IL-1 and TNFalpha serve as equally important mediators of hapten-induced alteration of LC behaviors. Motile activities of epidermal LCs are reprogrammed by selected cytokines known to be produced by keratinocytes under pathological conditions.

Inhibition of Langerhans cell ATPase and contact sensitization by lanthanides--role of T-suppressor cells.

Lanthanides are rare earths, elements 55-71 in the periodic table, that are of interest in biologic systems as isomorphic competitors for calcium binding sites. Lanthanides were tested for their inhibitory influence on the Ca++/Mg(++)-dependent ATPase of epidermal langerhans cells in vitro, and on the immunologic function of Langerhans cells in vivo. The trivalent ions of lanthanides, lanthanum, and cerium completely inhibited the ATPase staining of Langerhans cells in vitro. When mice were sensitized with dinitrofluorobenzene on skin sites pretreated with topical lanthanum chloride, and challenged on untreated ear skin, a markedly reduced contact hypersensitivity response was observed. This hyporesponsiveness was found to be antigen specific, and could be passively transferred to naive syngeneic animals recipients by CD4-CD8+ spleen cells. These results suggest that inhibition of the epidermal Langerhans cell surface ATPase by application of topical lanthanum and the induction of antigen-specific immunologic tolerance may be related events.

Cyclosporine and murine allergic contact dermatitis.

Cyclosporine is a new antilymphocytic, immunosuppressive agent currently being used primarily in experimental and human organ transplantation. The current study evaluated the effect of systemically administered cyclosporine on a cutaneous T-cell-mediated disorder by using the murine model of allergic contact dermatitis to dinitrofluorobenzene. Cyclosporine was found to significantly inhibit the ear swelling response, whether the drug was given during the early sensitization period or at the time of antigenic challenge to fully sensitized mice. This suppressive effect was reversible when mice were rechallenged with dinitrofluorobenzene 96 hours after the first challenge. Cyclosporine was not effective if given to sensitized animals as late as six hours after challenge. Lastly, the observed inhibition of the ear swelling response to cyclosporine closely paralleled a diminished degree of inflammation seen histopathologically.

Effect of Pyeongwee-San (KMP6) on 2,4-dinitrofluorobenzene-induced atopic dermatitis-like skin lesions in NC/Nga mice.

AIMS: Recently, some studies reported that digestive tract disease is closely associated with atopic dermatitis (AD). Pyeongwee-San (KMP6) is a Korean medicine, which has come onto the drugstore for the treatment of digestive tract disease. The aim of the present study was to examine whether KMP6 could suppress 2,4-dinitrofluorobenzene (DNFB)-induced AD-like skin lesions in NC/Nga mice. MAIN METHODS: Mice were sensitized with DNFB by applying to shaved dorsal skin. At that time, the drugs or saline were orally administrated to DNFB-applied mice. KEY FINDINGS: The administration of KMP6 or glycyrrhizic acid (GL), a major component of KMP6, inhibited the scratching number in DNFB-induced AD model. The mRNA expressions of interleukin (IL)-4, interferon (IFN)-γ, tumor necrosis factor (TNF)-α, and CCR3 were upregulated by DNFB sensitization, but the upregulated mRNA expressions were significantly reduced by the administration of KMP6 or GL. In addition, the levels of IgE, histamine, and IL-4 were significantly reduced by the administration of KMP6 or GL in serum of DNFB-induced AD model. However, the level of IFN-γ in serum was significantly increased by KMP6 or GL. KMP6 or GL also significantly inhibited the numbers of inflammatory cells, mast cells, and protein level of IL-4 in lesions of DNFB-induced AD model. Finally, KMP6 or GL significantly decreased the productions of IL-4, IFN-γ, and TNF-α in anti-CD3 plus anti-CD28 antibody-stimulated splenocytes. SIGNIFICANCE: KMP6 showed anti-atopic potential in this setting; hence we suggest it as a potential prospect for anti-atopic agent besides being just a medicine for the stomach and bowels.

Rosmarinic acid attenuates 2,4-dinitrofluorobenzene-induced atopic dermatitis in NC/Nga mice.

Atopic dermatitis (AD) is one of the most common skin diseases, and its incidence is increasing in industrialized countries. Furthermore, the epicutaneous application of a hapten, such as 2,4-dinitrofluorobenzene (DNFB), evokes an AD-like lesion in NC/Nga mice under specific pathogen-free (SPF) conditions. Rosmarinic acid (RA) is a secondary metabolite that is frequently found in herbs, and has anti-inflammatory, anti-oxidant, and anti-microbial effects. In this study, we studied whether RA is an effective treatment against DNFB-induced AD-like skin lesions in NC/Nga mice. RA at 1 or 5 µM was found to suppress the productions of interferon (IFN)-γ and interleukin (IL)-4 significantly by activated CD4(+) T cells. Furthermore, an intraperitoneal injection of RA at 10 or 50 mg/kg significantly inhibited skin lesion development and ear thickness and total serum IgE level increases in DNFB-treated NC/Nga mice. In addition, intraperitoneal administered RA at 10 or 50 mg/kg significantly inhibited the infiltrations of CD4(+) T, CD8(+) T, and mast cells into DNFB-induced skin lesions in NC/Nga mice. This study suggests that RA suppresses the development of AD-like dermatitis in DNFB-treated NC/Nga mice by reducing IFN-γ and IL-4 production by activated T cells and total serum IgE levels.

Oral administration of Astragalus membranaceus inhibits the development of DNFB-induced dermatitis in NC/Nga mice.

Epicutaneously administered chemical antigens like 2,4-dinitrofluorobenzene (DNFB), evoke an atopic dermatitis (AD)-like dermatitis reaction in NC/Nga mice under specific pathogen free (SPF) conditions. Astragalus membranaceus (AM), is a popular herbal medicine used to treat allergic diseases in East Asia. In the present study, we examined whether AM suppress AD-like skin lesions in NC/Nga mice treated with DNFB under SPF conditions. Oral administration of AM to DNFB-treated NC/Nga mice was found to inhibit ear thickness increases and the skin lesions induced by DNFB. Moreover, IFN-gamma production by CD4(+) T cells from the lymph nodes of DNFB-treated NC/Nga mice was significantly inhibited by AM treatment, although levels of IL-4 and total IgE in serum were not. Study findings suggest that AM may suppress the development of AD-like dermatitis in DNFB-treated NC/Nga mice by reducing IFN-gamma production.

Anti-allergic effects of cnidii monnieri fructus (dried fruits of Cnidium monnieri) and its major component, osthol.

Anti-allergic effects (types I and IV) of the 70% ethanol extract (CM-ext) obtained from Cnidii Monnieri Fructus (dried fruits of Cnidium monnieri) were investigated on 48 h homologous passive cutaneous anaphylaxis (PCA), 2, 4-dinitrofluorobenzene (DNFB)-induced contact dermatitis and picryl chloride (PC)-induced contact dermatitis in experimental animals. CM-ext showed inhibitory effects on these allergic models. Osthol isolated from CM-ext also had the inhibitory effects. These results suggested that Cnidii Monnieri Fructus might be useful as an agent for allergic diseases and that its anti-allergic effect was partially attributable to a coumarin derivative, osthol.

Xantina oxidasa hepática: experiencias con inhibidores / Liver xanthine oxidase: experiences with inhibitors

Los grupos amino de la XOD (Xantina oxidasa) del hígado de rata son inhibidos por reactivos como el benzaldehído y el 2,4-dinitrofluorbenceno. Esta inhibición ocurre más rápidamente a elevados pH y es progresiva e irreveersible. Estos reactivos atacan grupos amino de la XOD, pero no se excluye que haya otros grupos que puedan ser bloqueados. Si se representa la inhibición en función de la unión con el benaldehído o 2,4-dinitrofluorbenceno, se observa que una fracción relativamente pequeña del total de grupos amino de la XOD es más reactiva a esta inhibició y que estos grupos amino se modifican por estos inhibidores. Los estudios de unión del benzaldehído sugieren dos clases de actividad enzimática, presentes en igual proporción, pero difieren en su sensibilidad frente al benzaldehído. Los parámetros cinéticos de la actividad residual de la XOD tratada con benzaldehído se asemejan a los de la enzima nativa, excepto el comprotamiento inhibitorio frente a altas concentraciones de sustrato

Xantina oxidasa hepática: experiencias con inhibidores / Liver xanthine oxidase: experiences with inhibitors

Los grupos amino de la XOD (Xantina oxidasa) del hígado de rata son inhibidos por reactivos como el benzaldehído y el 2,4-dinitrofluorbenceno. Esta inhibición ocurre más rápidamente a elevados pH y es progresiva e irreveersible. Estos reactivos atacan grupos amino de la XOD, pero no se excluye que haya otros grupos que puedan ser bloqueados. Si se representa la inhibición en función de la unión con el benaldehído o 2,4-dinitrofluorbenceno, se observa que una fracción relativamente pequeña del total de grupos amino de la XOD es más reactiva a esta inhibició y que estos grupos amino se modifican por estos inhibidores. Los estudios de unión del benzaldehído sugieren dos clases de actividad enzimática, presentes en igual proporción, pero difieren en su sensibilidad frente al benzaldehído. Los parámetros cinéticos de la actividad residual de la XOD tratada con benzaldehído se asemejan a los de la enzima nativa, excepto el comprotamiento inhibitorio frente a altas concentraciones de sustrato (AU)