Topical effects of roflumilast on 1-chloro-2,4-dinitrobenzene-induced atopic dermatitis-like skin lesions in NC/Nga mice

Phosphodiesterase-4 (PDE-4) inhibitors have a wide range of anti-inflammatory and immunomodulatory activities. Here we examined the effects of roflumilast, a well-known PDE-4 inhibitor, on 1-chloro-2,4-dinitrobenzene (DNCB)-induced atopic dermatitis-like lesions. Roflumilast inhibited DNCB-stimulated IL-1alpha secretion in HaCaT cells, and reduced ear thickness and lymph node weights in BALB/c mice sensitized with DNCB. Topical application of roflumilast to DNCB-induced atopic dermatitis-like skin lesions of NC/Nga mice ameliorated intensity scores and dorsal skin thickness, in parallel with reduced tissue IL-1beta levels and epidermal hyperplasia. On the other hand, no effect on IgE and IL-4 was observed upon roflumilast treatment. Taken together, roflumilast showed beneficial effects against DNCB-induced atopic dermatitis.     

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 royal jelly inhibits the development of atopic dermatitis-like skin lesions in NC/Nga mice

We have shown previously that in addition to IL-4, IL-5 and IL-10, antigen-specific interferon-gamma (IFN-gamma) production by spleen cells from ovalbumin (OVA)/Alum-immunized mice is inhibited by the administration of royal jelly (RJ). Since it has been shown that both Th1 and Th2 cytokines play pathogenic roles in the generation of atopic dermatitis (AD), we have examined whether RJ suppresses the development of AD-like skin lesions in NC/Nga mice induced by repeated application of picryl chloride (PiCl) under specific pathogen-free (SPF) conditions. Oral administration of RJ to the PiCl-treated NC/Nga mice inhibited the development of AD-like skin lesions in these mice as exemplified by the significant decrease in the total skin severity scores and the decrease in hypertrophy, hyperkeratosis, and infiltration of the epidermis and corium by inflammatory cells. IFN-gamma production by spleen cells from PiCl-treated NC/Nga mice in response to TNP-KLH was partially but significantly inhibited by the oral administration of RJ, while IFN-gamma production by Con A-stimulated spleen cells was not affected. Since inducible nitric oxide (NO) synthase (iNOS)-derived NO has been suggested as an important immunoregulatory mediator in inflammatory autoimmune diseases, we have also examined the expression of iNOS in the dorsal skin lesions of PiCl-treated NC/Nga mice. Interestingly, the expression of iNOS was significantly increased in the skin lesions of RJ-administered mice compared with those of control PBS-administered mice. Thus, our results suggest that RJ suppresses the development of AD-like skin lesions in PiCl-treated NC/Nga mice, possibly by a combination of down-regulating TNP-specific IFN-gamma production and up-regulating iNOS expression.     

Epigallocatechin-3-gallate improves Dermatophagoides pteronissinus extract-induced atopic dermatitis-like skin lesions in NC/Nga mice by suppressing macrophage migration inhibitory factor

Epigallocatechin-3-gallate (EGCG) has been shown to exert anti-inflammatory effects on the inflammatory skin conditions. However, little is known about its effect on atopic dermatitis (AD). We first attempted to assess the anti-inflammatory effect of topical application of EGCG in vivo AD model using NC/Nga mice and to determine whether EGCG exerts the anti-inflammatory effect by inhibiting macrophage migration inhibitory factor (MIF) and other cytokines that are related to immune dysregulation in the pathogenesis of AD. Murine AD-like skin lesions were made by painting Dermatophagoides pteronissinus extract (DPE). The effects of EGCG treatment were assessed by total clinical severity score and ear thickness, and by histological grading. In addition, the mRNA and protein expression of the cytokines including MIF were measured by real-time RT-PCR and immunohistochemistry. The serum levels of MIF and IgE were measured by ELISA. In the AD mouse model, EGCG significantly reduced the total clinical severity score and ear thickness (p<0.05). The histological grading was also markedly improved. The mRNA expression of MIF, TNF-alpha, IFN-gamma, IL-2 and IL-12 p40, but not of IL-4, IL-5 and IL-13 in the lesions was significantly reduced by EGCG (p<0.05). On the immunohistochemistry, EGCG also markedly diminished the expression of MIF, TNF-alpha and IFN-gamma. The serum MIF and IgE production was significantly reduced by EGCG (p<0.05). These results demonstrate that topical application of EGCG may improve the AD-like skin lesions by suppressing MIF and T helper 1 cytokines. Taken together, it is suggested that EGCG may be a potential therapeutic modality for AD.     

Topical application of a novel ceramide derivative, K6PC-9, inhibits dust mite extract-induced atopic dermatitis-like skin lesions in NC/Nga mice

Atopic dermatitis (AD) is a chronic inflammatory skin disease. K6PC-9 (N-Ethanol-2-hexyl-3-oxo-decanamide) is a novel synthetic ceramide derivative of PC-9S (N-Ethanol-2-mirystyl-3-oxo-stearamide), which was known to be effective in atopic and psoriatic patients. To investigate the immunomodulatory activity of K6PC-9, we examined the effect of K6PC-9 on T lymphocyte and macrophage function and the effect of topical application of K6PC-9 on skin inflammation and AD-like skin lesions in mouse models. K6PC-9 had no effect on concanavalin A-induced proliferation, interleukin (IL)-2 secretion and IL-4 secretion in mouse splenocytes. In contrast, lipopolysaccharide-induced nitrite generation was potently suppressed by K6PC-9 in mouse peritoneal macrophages. In mouse model of skin inflammation, K6PC-9 inhibited phorbol ester-induced increase in ear thickness and expression of tumor necrosis factor-alpha in the ear of BALB/c mice. Topical application of K6PC-9 also suppressed mite extract-induced AD-like skin lesions in NC/Nga mice. Increase in ear thickness was significantly inhibited by K6PC-9 in this model. K6PC-9 also blocked the infiltration of mast cells and neutrophils into the ear. Further study demonstrated that the mRNA expression of tumor necrosis factor-alpha and adhesion molecules, such as vascular cell adhesion molecule-1, intercellular adhesion molecule-1, E-selectin, was also suppressed by K6PC-9 in the ear of mite extract-treated NC/Nga mice. Taken together, the results presented in this report show that K6PC-9 has an anti-inflammatory potential and exerts beneficial effects in an animal model of AD, indicating that K6PC-9 might be used as a topical agent for the treatment of AD.     

Effect of Lactobacillus acidophilus strain L-55 on the development of atopic dermatitis-like skin lesions in NC/Nga mice

In this study, we examined whether Lactobacillus acidophilus strain L-55 (strain L-55) suppresses the development of atopic dermatitis (AD)-like skin lesions induced by repeated application of 2,4,6-trinitrochlorobenzene (TNCB) in sensitized NC/Nga mice. The effect of strain L-55 was assessed by measuring clinical symptoms, ear swelling, scratching behavior and serum levels of total IgE. Strain L-55 was administered orally once a day: Strain L-55 at doses of 1 and 10 mg cells/mouse inhibited the development of AD-like skin lesions in dermatitis scores for the back. The increase of dermatitis score and ear swelling was also inhibited by strain L-55. In addition, strain L-55 also caused an inhibition of histological changes induced by repeated application of TNCB. Scratching behavior observed in the back and ear was inhibited by strain L-55. Furthermore elevated serum IgE levels observed by TNCB were also decreased by strain L-55. These results indicate that the inhibition of strain L-55 on AD-like lesions induced by repeated application of TNCB in sensitized NC/Nga mice occurred via a decrease in the serum total IgE level.     

mAgK114 suppresses lymphocyte infiltration into epidermis in the picryl chloride-induced atopic dermatitis-like skin lesions of NC/Nga mice

BACKGROUND: We have previously shown that when mouse AgK114 (mAgK114, a glycosylphosphatidylinositol anchored membrane-associated protein) is applied to the wound area, the inflammatory responses in the early recovery phase of damaged tissue are enhanced and wound closure is accelerated. This suggests that mAgK114 has an important effect on skin wound repairing. MATERIALS AND METHODS: Whether mAgK114 supresses the development, in NC/Nga mice, of atopic dermatitis (AD)-like skin lesions induced by repeated application of 2,4,6-trinitrochlorobenzene (picryl chloride, PiCl) was examined under specific pathogen-free conditions. RESULTS: Histopathologically, the application of mAgK114-ointment to the PiCl-treated NC/Nga mice remarkably suppressed severe lymphocytic infiltration into the epidermis, although total skin severity scores, histological changes in hypertrophy, erosion and infiltration of inflammatory cells into the corium and subcutaneous tissues were comparable between the mAgK114-treated group of mice and the control group. CONCLUSION: Our results suggest that mAgK114 would be beneficial for the treatment of atopic dermatitis by suppressing severe lymphocytic infiltration into the epidermis.     

Therapeutic application of human leukocyte antigen-G1 improves atopic dermatitis-like skin lesions in mice

Human leukocyte antigen (HLA)-G is an immune checkpoint molecule that plays critical roles in immune response and in triggering inhibitory signaling to immune cells such as T cells, natural killer cells, and antigen-presenting cells. Thus, the application of HLA-G can be considered for treating immune response-related inflammatory disorders. We have previously reported that treatment with HLA-G1 and HLA-G2 ameliorates the joint swelling associated with collagen-induced arthritis of DBA/1 mice, an animal model for rheumatoid arthritis. In this study, we further investigated the effects of HLA-G1 on atopic dermatitis (AD), the most common inflammatory skin disorder. AD-like lesions were induced with the extract of the house dust mite Dermatophagoides farinae in NC/Nga mice. Continuous administration of HLA-G1 ameliorated the AD-like skin lesions in the mice. Furthermore, production of immunoglobulin E, interleukin (IL)-13, and IL-17A was significantly reduced in HLA-G1-treated mice, suggesting a Th2/Th17-mediated immune-inhibitory function of HLA-G1 in vivo. Our studies shed light on novel therapeutic strategies with recombinant HLA-G proteins for immune reaction-mediated chronic inflammatory disorders.     

Effects of topically applied Korean red ginseng and its genuine constituents on atopic dermatitis-like skin lesions in NC/Nga mice

Ginseng (the root of Panax ginseng C.A. Meyer, family Araliaceae) possesses various biological activities, including anti-inflammatory and anti-tumor actions. However, their topical effect on atopic dermatitis (AD) has not been studied yet. The aim of this study was to examine the therapeutic effects of topical Korean red ginseng saponin fraction (KRGS) and its genuine constituents on AD-like skin lesions in an AD mouse model. The therapeutic effect of topical KRGS and ginsenosides in 2-chloro-1,3,5-trinitrobenzene (TNCB)-treated NC/Nga mice was assessed by measuring the skin severity scores, ear thickness, histological changes of lesional skin including mast cell count, tissue tumor necrosis factor (TNF)-α, interleukin (IL)-4, and interferon (IFN)-γ mRNA expression, and total serum IgE. Topical administration of 0.1% KRGS, 0.1% Rh2 and 0.1% Rh2+0.1% Rg3 significantly reduced the clinical skin severity scores, ear thickness and mast cell infiltration in the TNCB-induced AD-like skin lesions. Topical application of KRGS and its constituents significantly reduced TNCB-induced increase in ear TNF-α and IL-4 mRNA expression, but not IFN-γ mRNA expression. There was little change of serum total IgE level by topical KRGS and its constituents. In this study, topical KRGS and ginsenosides Rh2 and Rg3 were found to exert an anti-inflammatory effect in vivo and proved to be beneficial in an animal model of AD. Our results suggest that KRGS and its ginsenosides Rh2 and Rg3 have potential as a topical agent for the treatment of AD.     

Luffa cylindrica suppresses development of Dermatophagoides farinae-induced atopic dermatitis-like skin lesions in Nc/Nga mice

Abstract

Context: The fruit pulp of Luffa cylindrica Roemer (Cucurbitaceae) (LC) has been used to induce hemostasis, resolve phlegm and clear fever in traditional Korean medicine. However, the efficacy of LC has not been examined in atopic dermatitis (AD).

Objective: A 70% ethanol extract of LC was evaluated to determine anti-inflammation and anti-AD effects in vitro and in vivo.

Materials and methods: The inhibitory effects of LC on the production of PGE₂ and histamine were respectively measured in lipopolysaccharide-treated (1?μg/mL) RAW264.7 macrophages and phorbol-12 myristate 13-acetate (50?nM) and A23187 (1?µM)-stimulated HMC-1 mast cells. The production of AD-related chemokines (RANTES, TARC, and MDC) were evaluated in IFN-γ and TNF-α-stimulated (10?ng/mL, each) HaCaT keratinocytes. LC (10?mg/mouse/d) was topically applied to the dorsal skin and ears of Dermatophagoides farina (Pyroglyphidae)-sensitized Nc/Nga mice for 4?weeks.

Results: The IC₅₀ values of LC on PGE₂ and histamine production were 16.89 and 139.9?μg/mL, individually. The production of TARC and RANTES were inhibited 20% and 12% by LC (50?μg/mL) in HaCaT cells, respectively (p?<?0.05). In sensitized-NC/Nga mice, the plasma levels of IgE and histamine were suppressed 36% and 41% by LC, respectively (p?<?0.05). LC also reduced hemorrhage, hypertrophy, and hyperkeratosis of the epidermis and infiltration of mast cells in the dorsal skin and ear.

Discussion and conclusion: LC can inhibit AD-like skin lesions and reduce the generation of IgE via inhibition of the inflammatory responses. LC has potential as a therapeutic agent to treat allergic diseases, including AD.     

Immunosuppressive effects of fisetin against dinitrofluorobenzene-induced atopic dermatitis-like symptoms in NC/Nga mice

Atopic dermatitis (AD) is a multifactorial chronic skin disorder that is increasing in prevalence globally. In NC/Nga mice, repetitive epicutaneous applications of 2-4-dinitrofluorobenzene (DNFB) induces AD-like clinical symptoms. Bioflanonol fisetin (3,7,3′,4′-tetrahydroxyflavone) is a dietary component found in plants, fruits and vegetables. Fisetin has various physiological effects that include anti-oxidation, anti-angiogenesis, anti-carcinogenesis and anti-inflammation. In this study, we investigated whether fisetin relieves AD-like clinical symptoms induced by repeated DNFB treatment in NC/Nga mice. Fisetin significantly inhibited infiltration of inflammatory cells including eosinophils, mast cells and CD4⁺ T and CD8⁺ T cells, and suppressed the expressions of cytokines and chemokines associated with dermal infiltrates in AD-like skin lesions. Total serum immunoglobulin E (IgE) levels and the ratio of phospho-NF-κB p65 to total NF-κB p65 were markedly reduced by fisetin. Fisetin also reduced the production of interferon-gamma and interleukin-4 by activated CD4⁺ T cells in a dose-dependent manner, whereas the anti-inflammatory cytokine, interleukin-10 was increased. These results implicate fisetin as a potential therapeutic for AD.     

Inhibitory effects of Saururus chinensis (LOUR.) BAILL on the development of atopic dermatitis-like skin lesions in NC/Nga mice

The present study was performed to examine whether the leaves of Saururus chinensis (LOUR.) BAILL (SC), an herb used for the management of various skin diseases including atopic dermatitis (AD) in Eastern countries, inhibited the development of AD-like skin lesions in NC/Nga mice which was induced by repeated application of picryl chloride (PiCl). The efficacy of SC was judged by measurement of skin severity, itching behavior, histological study, serum IgE levels, IL-4 and IFN-gamma in lymph nodes. Oral administration of SC extract to the PiCl-treated NC/Nga mice for 8 weeks (5 d per week) inhibited significantly the development of AD-like skin lesions macroscopically. Histologically, SC inhibited dermatitis changes like hypertrophy, hyperkeratosis, and infiltration of inflammatory cells into epidermis and dermis. The itching behavior and serum IgE level decreased significantly after SC administration. SC administration enhanced IFN-gamma mRNA expression but did not have an effect on IL-4 mRNA expression. These results suggest that SC could inhibit the development of AD-like skin lesions in NC/Nga mice possibly through modulating the Th1/Th2 imbalance by the promoting of Th1 cell response. Thus, SC may be an alternative substance for the management of AD patients.     

Omega-3 fatty acid-derived mediator,Resolvin E1, ameliorates 2,4-dinitrofluorobenzene-induced atopic dermatitis in NC/Nga mice

Atopic dermatitis (AD) is a common inflammatory skin disease for which few effective treatments are available. Resolvin E1 (RvE1; 5S,12R,18R-trihydroxy-6Z,8E,10E,14Z,16E-eicosapentaenoic acid) is an endogenous lipid mediator derived from omega-3 fatty eicosapentaenoic acid, which is a potent inhibitor of inflammation. AD-like skin lesion was induced by repetitive skin contact with DNFB in NC/Nga mice and the effects of RvE1 were evaluated on the basis of histopathological findings of skin, ear swelling and cytokine production of CD4⁺ T cells. Intraperitoneal injection of RvE1 for one week after DNFB challenge significantly lowered ear swelling and improved back skin lesions. In addition, RvE1 significantly suppressed production of interferon-gamma (IFN-γ) and interleukin-4 (IL-4) by activated CD4⁺ T cells and serum IgE level. Furthermore, RvE1 reduced DNFB-induced infiltration of eosinophils, mast cells, CD4⁺ T cells, and CD8⁺ T cells in skin lesions.Therefore, RvE1 may suppress the development of AD-like skin lesions in DNFB-treated NC/Nga mice by reducing IL-4 and IFN-γ of activated CD4⁺ T cells and serum IgE levels and infiltration of immune cells to skin lesion.     

Mechanism underlying the effect of combined therapy using glucosamine and low-dose cyclosporine A on the development of atopic dermatitis-like skin lesions in NC/Nga mice

Combination therapy is often used in the treatment of atopic dermatitis (AD) to improve clinical efficacy or to spare the dose of each drug. Cyclosporine A (CsA) is a calcineurin inhibitor that was developed for the treatment of AD. Glucosamine (Glu) is a potent immunosuppressant that inhibits Th2-mediated immunity. We previously reported that Glu has an ameliorative effect on the development of the pathology in NC/Nga mice. The aims of our study were to investigate the therapeutic efficacy of combination of Glu and low-dose CsA in dermatophagoides farina (Df)-induced AD-like skin lesions in NC/Nga mice and to determine the underlying therapeutic mechanisms. The Df-induced NC/Nga mice with a clinical score of 7 were used for treatment with Glu (500 mg/kg) alone, low-dose CsA (2, 5, and 10 mg/kg) or in combination. The clinical scores were reduced significantly by the combination treatment with Glu and low-dose CsA. The suppression of dermatitis by combined therapy was accompanied by decrease in the plasma level of IgE and in the splenic level of IL-4, IL-5, IL-13, TARC and eotaxin. Histological analysis of the skin also revealed that combination treatment significantly reduced the inflammatory cellular infiltrate, including mast cells and eosinophils. Particularly, immunological evaluation reveals an increase of CD4⁺CD25⁺ Treg cells in the combined treatment. The induction of TSLP, which leads to systemic Th2 response, was reduced in the skin on combination treatment. The protein expression of filaggrin and involucrin was recovered by combination treatment in the skin lesions, whereas the protein expression of keratin-10 and keratin-14 decreased in the combination treatment. Collectively, our findings suggest that combination treatment of Glu and low-dose CsA leads to the therapeutic effects in Df-induced AD-like skin lesion in NC/Nga mice through inhibition of IgE, inflammatory cellular infiltrate, and recovery of skin barrier function via a mechanism that may inhibition of Th2-mediated immune responses, in part, increment of CD4⁺CD25⁺ Treg cells. These results suggest that this combined immunosuppressive treatment may provide important implications for the design of therapeutic strategies aimed at AD treatment.     

The histone deacetylase inhibitor,trichostatin A,inhibits the development of 2,4-dinitrofluorobenzene-induced dermatitis in NC/Nga mice

Repetitive skin contact with a chemical hapten like 2,4-dinitrofluorobenzene (DNFB) evokes an atopic dermatitis (AD)-like dermatitis reaction in NC/Nga mice maintained under specific pathogen-free (SPF) conditions. The histone deacetylase (HDAC) inhibitor, trichostatin A (TSA), modulates the expression of several genes by inhibiting the activity of HDACs. Furthermore, TSA has been reported to suppress inflammatory cytokine expression and to induce T cell-suppression by increasing regulatory T cell (T reg cell) numbers. In addition, histone deacetylase inhibitors (HDACi) are currently undergoing clinical trials for the treatment of inflammatory disorders.     

Topical application of Pleurotus eryngii extracts inhibits 2,4-dinitrochlorobenzene-induced atopic dermatitis in NC/Nga mice by the regulation of Th1/Th2 balance

Pleurotus eryngii is a nutritional and medicinal food rich in polysaccharides that enhance the host immune system as a response to various diseases. The present study investigated the effects of P. eryngii extracts (PEE) on the progress of atopic dermatitis (AD)-like skin lesions in NC/Nga mice induced by 2,4-dinitrochlorobenzene (DNCB). We evaluated skin dermatitis severity, ear thickness, histopathological examination, and cytokines level in DNCB-applied mice treated with PEE. Continuous treatment of PEE inhibited the development of the AD-like skin lesions. PEE suppressed DNCB-induced dermatitis severity, serum level of IgE and thymus and activation-regulated chemokine (TARC), and mRNA expression of TNF-α, INF-γ, IL-4, IL-5, and IL-13 in mice. In addition, PEE reduced thickness of the dermis and dermal infiltration of inflammatory cells and mast cells in histopathological examination. These results indicate that PEE inhibits allergic contact dermatitis through the modulating of T helper (Th)1 and Th2 responses and diminishing the inflammatory cells and mast cells infiltration in the skin lesions in NC/Nga mice.     

Inhibition of atopic dermatitis by topical application of silymarin in NC/Nga mice

Silymarin has been known to inhibit chemical-induced irritant contact dermatitis. In the present study, we report that topical application of silymarin suppresses dust mite extract (DPE)-induced atopic dermatitis (AD) in NC/Nga mice. Repeated topical application of ears with DPE caused AD-like skin lesions in NC/Nga mice. However, silymarin reduced AD-like skin lesions in these mice, resulting in decreased ear swelling and leukocyte infiltration into the ear. Moreover, our results showed that mast cell infiltration into the ear was suppressed by silymarin treatment in DPE-treated NC/Nga mice. Silymarin also reduced plasma level of IL-4 and IgE in these mice. Further study demonstrated that the mRNA expression of IL-4 was increased and that of IFN-gamma was decreased by DPE treatment in the ears of NC/Nga mice. However, DPE-induced changes in IL-4 and IFN-gamma mRNA expression were reversed by silymarin. DPE-induced increase in TNF-alpha mRNA expression was also suppressed by silymarin treatment. The results presented in this report suggest that silymarin might be beneficial for the treatment of AD.     

Induction of atopic eczema/dermatitis syndrome-like skin lesions by repeated topical application of a crude extract of Dermatophagoides pteronyssinus in NC/Nga mice

Mite antigen has been considered to play important roles in the development of atopic eczema/dermatitis syndrome (AEDS). In the present study, we attempted to induce an AEDS-like skin lesion in mice using Dermatophagoides pteronyssinus crude extract (DPE) as an antigen and performed pathophysiological evaluations. Ears of mice were tape-stripped and DPE was painted 3 times a week. Eczematous skin lesion and ear swelling were apparent in NC/Nga mice treated with DPE after 2 weeks, whereas neither skin lesion nor ear swelling were observed in BALB/c mice even after 30 days. Histological evaluation demonstrated that edema, epidermal hyperplasia and the accumulation of inflammatory cells were apparent in the ears of DPE-treated NC/Nga mice. In contrast to skin lesion and ear swelling, total serum IgE levels were increased in both NC/Nga and BALB/c mice. Treatment with DPE also increased auricular lymph node weight in both NC/Nga mice and BALB/c mice. To further characterize, we analyzed cytokine mRNA expression in ears and lymph nodes of DPE-treated NC/Nga mice. Increased expression of IL-4 and TNF-alpha mRNA was observed in both ears and lymph nodes of NC/Nga mice treated with DPE. Additionally, there was no change in the responsiveness of BALB/c mice to DPE treatment by adaptive transfer of serum from DPE-treated NC/Nga mice to BALB/c mice. Taken together, our results indicate that eczematous skin lesion and ear swelling caused by repeated application of DPE in NC/Nga mice has a Th2-dominant background and that inflammation is involved in this process. The animal model of AEDS established in this report may be used to investigate the pathogenesis of AEDS and evaluate the potential therapeutic agents for AEDS.     

TCDD exposure exacerbates atopic dermatitis-related inflammation in NC/Nga mice

Our previous study showed that 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) exposure of NC/Nga mice, a mouse model of atopic dermatitis, induces no dermal changes. In the present study, to investigate whether TCDD exacerbates atopic dermatitis-like skin lesions elicited in NC/Nga mice, NC/Nga mice were applied with picryl chloride (PC), and then were exposed to a single oral dose of 0 (control), 5, and 20 microg TCDD/kg. Two weeks later, spleens, blood, and skin specimens were collected. TCDD exposure increased the production of Th1-type cytokine IFN-gamma, but not Th2-type cytokine IL-4, from spleen cells stimulated with a mitogen. The plasma total IgE antibody levels of the TCDD-exposed mice remained at control levels. On the other hand, TCDD exposure markedly increased the mast cell infiltration and degranulation in PC-sensitized NC/Nga mice histologically, as compared with control mice. These results suggest that TCDD exposure exacerbates atopic dermatitis-related inflammation with no increase of IgE antibody production and that TCDD may be one of the environmental pollutants that induce exacerbations of atopic diseases.