Transforming growth factor‐bβ1 suppresses atopic dermatitis‐like skin lesions in NC/Nga mice

BACKGROUND: Atopic dermatitis is a chronic, relapsing inflammatory disorder characterized by pruritic and eczematous skin lesions. Transforming growth factor (TGF)-beta1 has been implicated in the suppression of inflammatory responses. OBJECTIVE: The purpose of this study is to determine whether TGF-beta1 suppresses skin lesions in a mouse model of atopic dermatitis. METHODS: We used the NC/Nga strain of mice as an in vivo model of atopic dermatitis. The effects of exogenous TGF-beta1 on atopic dermatitis-like skin lesions in NC/Nga mice were evaluated clinically, histologically and immunologically. RESULTS: Subcutaneous injection of recombinant TGF-beta1 macroscopically suppressed eczematous skin lesions in NC/Nga mice associated with reduced serum immunoglobulin E (IgE) levels. Histological analysis showed that TGF-beta1 significantly inhibited the infiltration of inflammatory cells such as mast cells and eosinophils into the skin of NC/Nga mice. Spontaneous interferon (IFN)-gamma production from splenocytes of NC/Nga mice was down-regulated by the treatment with TGF-beta1 and neutralizing antibody against IFN-gamma inhibited skin lesions in NC/Nga mice. The inhibitory effect of TGF-beta1 on the skin lesions lasted at least 1 week after cessation of the treatment. CONCLUSION: These findings indicate that TGF-beta1 suppressed atopic dermatitis-like skin lesions in NC/Nga mice at least in part through down-regulation of IFN-gamma. These results suggest that TGF-beta1 may have a therapeutic potential for atopic dermatitis.     

Hyperresponsive TH2 cells with enhanced nuclear factor-kappa B activation induce atopic dermatitis-like skin lesions in Nishiki-nezumi Cinnamon/Nagoya mice

BACKGROUND: Nishiki-nezumi Cinnamon/Nagoya (NC/Nga) mice raised in nonair-controlled conventional circumstances spontaneously develop atopic dermatitis-like skin lesions; however, the underlying mechanisms remain unclear. OBJECTIVE: We wanted to identify the critical intracellular signaling molecules in T cells that induce atopic dermatitis-like skin legions in NC/Nga mice. METHODS: We examined the levels of signal transduction and cytokine production in T cells, particularly those in atopic dermatitis-like lesions induced by the topical injection of mite antigens in NC/Nga mice under specific pathogen-free conditions. RESULTS: In NC/Nga mice maintained under specific pathogen-free conditions, the capability of T(H)1/T(H)2 and T cytotoxic 1/T cytotoxic 2 (Tc1/Tc2) cell differentiation increased significantly. T-cell antigen receptor-mediated activation of the extracellular signal-regulated kinase/mitogen-activated protein kinase cascade and nuclear factor-kappaB (NF-kappaB) signaling were enhanced in NC/Nga T cells. The expression of T(H)2 cytokines (IL-4, IL-13, and IL-5) and that of GATA-binding protein 3 (GATA3), avian musculoaponeurotic fibrosarcoma (c-Maf), NF-kappaB, and activator protein 1 (AP1) selectively increased in draining lymph node T cells of NC/Nga mice. Moreover, the cell transfer of inhibitory NF-kappaB mutant-infected T(H)2 cells reduced ear thickness in the mite antigen-induced skin lesion of NC/Nga mice. CONCLUSION: Hyperresponsive T(H)2 cells with an enhanced activity of NF-kappaB and AP1 play a crucial role in the pathogenesis of atopic dermatitis-like skin lesions in NC/Nga mice. CLINICAL IMPLICATIONS: These results indicate potential therapeutic usefulness of developing selective inhibitors for NF-kappaB in the treatment of human atopic dermatitis.     

Development of atopic dermatitis-like skin lesion with IgE hyperproduction in NC/Nga mice

Atopic dermatitis (AD) usually develops in patients with an individual or family history of allergic diseases, and is characterized by chronic relapsing inflammation seen especially in childhood, association with IgE hyperproduction and precipitation by environmental factors. However, the exact etiology of AD has been unclear. To further explore the pathogenesis and treatment of AD, a suitable animal model is required. We found that skin lesions, which were clinically and histologically very similar to human AD, spontaneously appeared on the face, neck, ears and dorsal skin of inbred NC/Nga mice when they were raised in non-sterile (conventional) circumstances, but not under specific pathogen-free conditions. Plasma levels of total IgE in conventional NC/Nga mice were markedly elevated from 8 weeks of age, correlating with clinical skin severity of dermatitis. Immunohistochemical examination of the skin lesion showed increased numbers of mast cells and CD4+ T cells containing IL-4 necessary for IgE synthesis. Thus, NC/Nga mice suffered from dermatitis very similar to human AD with IgE hyperproduction, which may be triggered by some environmental factor(s).      

Atopic dermatitis-like skin lesions induced by topical application of mite antigens in NC/Nga mice.

BACKGROUND: Atopic dermatitis (AD) is a chronic relapsing inflammation usually observed in patients with an individual or a familial history of atopic diseases, precipitated by environmental factors including mite antigens (Ag). However, the exact etiology of AD is unclear. To further explore the pathogenesis and treatment of AD, a suitable animal model is necessary. In this study, we developed a new animal model of AD induced by mite Ag in NC/Nga mice. METHODS: We injected the extracts of mite Ag intradermally at the ventral side of the ear of SPF NC/Nga mice on days 0, 2, 4, 7, 9, 11, 14 and 16, and measured the clinical symptoms and the ear thickness. On day 18, we collected blood and submandibular lymph nodes (LN) of the immunized ear to perform a histochemical analysis, and to measure the plasma immunoglobulins and cytokines. RESULTS: The NC/Nga mice immunized with mite Ag suffered from AD-like skin lesions including erythema followed by edema, excoriation and scaling. The histological and immunohistochemical examinations of the affected skin showed epidermal hyperplasia with hyperkeratosis, severe infiltration of CD4+ T lymphocytes, eosinophils and macrophages, and degranulation of mast cells. The total plasma IgE level was markedly elevated in mite Ag-treated mice. LN cells of mice immunized with mite Ag synthesized IgE in an Ag-dependent manner and secreted interleukin-4 (IL-4) and IL-5 but not interferon-gamma. CONCLUSIONS: NC/Nga mice treated with mite Ag manifest clinical and immunological aspects similar to patients with AD, suggesting that this model is suitable for exploring the pathogenesis of human AD.     

Induction of atopic dermatitis-like skin lesion in NC/Nga mice--the influence of the skin barrier destroying solution to the induction of dermatitis]

NC/Nga mouse is well known as a mouse model for atopic dermatitis. In general, when NC/Nga mouse are raised under specific pathogen free (SPF) conditions no skin lesions are detected, but when under non-filtrated (conventional) condition, atopic dermatitis like skin lesions appear spontaneously. However, this dermatitis develops in 70-90% of mice (not 100%), which makes it difficult to perform reproducible experiments every time. This study was performed under SPF conditions, using the four solutions (2% SDS, 4% SDS, ethanol, acetone/ether) to destroy the skin barrier function, and thereafter, applying the extracted solution of mite: Dermatophagoides pteronyssinus, which is a very popular antigen in pathogenesis of human atopic dermatitis. The extracted solution of mite was applied repeatedly on the NC/Nga mice with a pretreatment of barrier destroying solution and after 8 weeks the mice developed severe dermatitis (clinical skin condition score of 7-10.2 points) with marked elevation of plasma IgE level, whereas mice coated only with the barrier destroying solution showed weak skin lesion with no elevation of plasma IgE level. BALB/c mice, which are employed as control, showed weak skin lesion (clinical skin condition score of 0-3.8 points) and slight elevation of plasma IgE level after repeated application of the extracted solution of mite with a pretreatment of the barrier destroying solution, whereas mice coated only with the barrier destroying solution showed weak skin lesion and the no elevation of plasma IgE level was observed. In this study, using several solutions to disturb the skin barrier function before applying the antigen, we have found a suitable condition and types of solutions in inducing dermatitis in NC/Nga mice.     

Glucosamine improved atopic dermatitis-like skin lesions in NC/Nga mice by inhibition of Th2 cell development

Dysregulated Th subset responses, characterized by Th2‐dominant allergic inflammation, are thought to be central to the pathogenesis of atopic dermatitis (AD). Glucosamine has been shown to have immunosuppressive properties, but its effect on AD has not been examined. In this study, the immunoregulatory effects of glucosamine, using dermatophagoides farinae (Df)‐induced AD‐like skin lesions in NC/Nga mice, were investigated. The clinical scores were reduced significantly by the treatment with glucosamine at 10 and 20 mg/day. Histological analysis of the skin also revealed that treatment of glucosamine at 10 and 20 mg/day significantly reduced the inflammatory cellular infiltrate, including mast cells and eosinophils. The levels of serum IgE and Th2 cytokines in spleen cells were reduced, whereas no significant change was detected in IFN‐γ, a Th1 cytokine. To determine the mechanism associated with inhibition of the Th2 immune response, the effects of glucosamine on the selective differentiation pathway of the Th subset in vitro was examined in NC/Nga mice. The results showed that glucosamine suppressed the differentiation of naïve CD4⁺ T cells to Th2 cells in vitro. On the basis of in vivo and in vitro results of the NC/Nga mice, the immunobiological effects of glucosamine on peripheral blood mononuclear cells from patients with AD were examined. The production of Th2 cytokines, such as IL‐4 and IL‐5, was significantly decreased after in vitro administration of glucosamine, which suggest that glucosamine might be a useful immunomodulatory agent for the treatment of human AD.     

Role of substance P in an NC/Nga mouse model of atopic dermatitis-like disease

BACKGROUND: Atopic dermatitis (AD) can be exacerbated or induced in genetically predisposed individuals by psychological stress, which causes the release of substance P (SP). Therefore, SP may play an etiological role in the mechanisms underlying AD. METHODS: Changes in the number of mast cells and SP-containing mast cells in lesional skin, and the serum concentrations of SP and IgE during the development of AD-like disease up to 8 weeks after the start of picryl chloride (PiCl) induction in NC/Nga mice were examined. RESULTS: Clinical signs and symptoms seen in PiCl-treated NC/Nga mice as a model of AD-like disease began with erythema and haemorrhage, followed by oedema, superficial erosion, deep excoriation, scaling and dryness of the skin, as well as retarded growth, and the changes were exacerbated with an increase in the number of PiCl applications. An increase in the number of mast cells and eosinophil infiltration was observed in the lesional skin. The increase in SP-positive mast cells in the dermis in this model was significant from 1 week after the start of induction treatment, compared with intact mice, and SP-positive nerve fibres were observed in the dermis. CONCLUSION: SP is a crucial mediator of both dermatitis and scratching behaviour in this model.     

Toxoplasma gondii Infection Suppresses House Dust Mite Extract-Induced Atopic Dermatitis in NC/Nga Mice

Purpose

Toxoplasma gondii (T. gondii) is an obligate intracellular protozoan parasite that infects humans and animals via congenital or postnatal routes, and it is found worldwide. Modulation of the immune system by parasite infection is proposed to suppress allergic inflammation. Growing evidences have shown that interleukin (IL)-10-producing regulatory B cells (B_regs) and CD4⁺CD25⁺FoxP3⁺ regulatory T cells (T_regs) induced by parasite infection play a critical role in allergic or autoimmune diseases because these cells regulate negatively cellular immune responses and inflammation. Currently, the role of IL-10-producing regulatory B cells in host immune response during T. gondii infection is unknown. In this study, we investigate whether T. gondii infection can suppress the development of unrelated atopic dermatitis (AD)-like lesions.

Methods

AD is a chronically relapsing inflammatory skin disease accompanied by severe itching; for this, we used NC/Nga mice, a well-known experimental model of systemic AD. Repeated exposure to Dermatophagoides farinae crude extract (DfE), known as a major environmental allergen, evokes AD-like skin lesions in NC/Nga mice under specific pathogen-free conditions. NC/Nga mice were intraperitoneally infected with 10 cysts of T. gondii.

Results

T. gondii infection significantly ameliorated AD-like skin lesions in NC/Nga mice. The subpopulation of B_regs and T_regs in the AD mice was expanded in the course of T. gondii infection. In addition, T. gondii infection inhibited Th2 and enhanced Th1 immune response in the DfE-treated AD mice.

Conclusions

We have experimentally demonstrated for the first time that T. gondii infection ameliorated AD-like skin lesions in a mouse model of AD. Our study could in part explain the mechanisms of how parasite infection prevents the development of allergic disorder. Therefore, these immunemechanisms induced by T. gondii infection may be beneficial for the host in terms of reduced risk of allergic immune reactions.     

Chymase inhibitor improves dermatitis in NC/Nga mice

BACKGROUND: Mast cell chymase is thought to participate in allergic inflammation, but its precise role remains undetermined. Inbred NC/Nga mice develop skin lesions similar to atopic dermatitis (AD) when they grow up in a conventional environment. To elucidate the possible role of chymase in AD, we examined the effect of a chymase inhibitor on skin lesions of NC/Nga mice. METHODS: NC/Nga mice were given the chymase inhibitor SUN-C8257 daily at 150 mg/kg/day with drinking water, and the severity of the dermatitis was evaluated on day 35 of the experiment. The role of chymase in dermatitis was further investigated in vitro and in vivo using recombinant mouse mast cell protease-4 (mMCP-4). RESULTS: Administration of SUN-C8257 significantly reduced the clinical skin and histological score in NC/Nga mice. SUN-C8257 also inhibited the accumulation of inflammatory cells, such as eosinophils and mast cells, in the affected lesions in this model. mMCP-4 stimulated eosinophil migration in vitro, and intradermal injection of the enzyme resulted in a significant accumulation of inflammatory cells, including eosinophils, at the injection site. Thus amelioration of the skin lesions in NC/Nga mice by SUN-C8257 might be, at least in part, due to the suppression of cell infiltration in the lesions. CONCLUSION: Mast cell chymase may contribute to the pathogenesis of AD, and SUN-C8257 will be beneficial to the treatment of the skin disorder.     

A mouse model of the atopic eczema/dermatitis syndrome by repeated application of a crude extract of house-dust mite Dermatophagoides farinae

BACKGROUND: We cultured Dermatophagoides farinae (Df), one of the most common mites in house dust and the most important allergen among natural allergens. With this material, we attempted to produce an animal model of the atopic eczema/dermatitis syndrome (AEDS). METHODS: We cultured Df mites in high density and prepared a crude extract of Df (DfE) together with the culture medium. We applied the extract to the back skin of NC/Nga and BALB/c mice three times per week for 8 weeks. RESULTS: In the NC/Nga group, dryness or scaling appeared on the skin, and scratching behavior increased at the second week in the DfE-treated group. Skin erosion and hemorrhage occurred at the fourth week. The epidermis thickened and deepened into the upper dermis, in which mast cells were highly accumulated, corresponding with the skin lesion of AEDS patients. Specific IgE and IgG to DfE and total IgE were elevated in the sera. Mice treated with an extract of mite culture medium did not develop skin lesions. In the BALB/c group, mice developed specific IgE and IgG to DfE, however, no typical skin lesions appeared. Mast cells in the upper dermis did not increase. CONCLUSIONS: Repeated painting of Dermatophagoides extract produced IgE-associated AEDS-like lesions on the skin of NC mice.     

Improvement of atopic dermatitis in NC/Nga mice by topical application of CpG phosphodiester-ODN

Atopic dermatitis (AD) is a chronic inflammatory skin disease with pruritic and eczematous lesions characterized by increased total IgE level, inflammatory cell infiltration, and the elevated expression of Th2 cytokines. Synthetic oligodeoxynucleotides containing unmethylated CpG dinucleotides are known to have immunostimulatory activities in mice and to convert from Th2 to Th1 immune responses in AD. Previous work has shown clinical effectiveness of CpG phosphorothioate-ODN in AD mice model. However, due to longer in vivo half-life and the possibility of causing unwanted side effects, therapeutic use of CpG phosphorothioate-ODN can be limited. Thus, we investigated the efficacy of CpG phosphodiester-ODN with a novel sequence in NC/Nga mice. Topical application of phosphodiester-ODN penetrated rapidly from epidermis to the lymph nodes, accompanied by reduced infiltration of inflammatory cells and decreased number of cells expressing cytokines such as IL-4, IL-10 and IFN-gamma. Furthermore, the expression of IFN-gamma was reduced in the CpG ODNs-treated NC/Nga mice while the expression of IL-12p40 was increased, suggesting stimulation of Th1 immune response. The expression of IL-10 was strongly reduced, which meant the suppression of Th2 immune response in NC/Nga mice, accompanied by reduced level of IgE and IgG1, but increased level of IgG2a in sera. Since phosphodiester-ODN has been shown to cause minimum side effect comparing its phosphorothioate counterpart, it is proposed to become a new therapeutic modality for AD.     

Effects of TNCB sensitization in DS-Nh mice, serving as a model of atopic dermatitis, in comparison with NC/Nga mice

BACKGROUND: It has been predicted that a type-1 and type-2 helper T cell (Th1/Th2) imbalance exists in atopic dermatitis (AD). In DS-Nh mice, an AD mouse model, Staphylococcus aureus increases on the skin surface. OBJECTIVE: To investigate whether the Th1-dominant response has an influence on the development of AD, we induced chronic allergic hypersensitivity with 2,4,6-trinitrochlorobenzene (TNCB ) in two AD mouse models: NC/Nga mice and DS-Nh mice. Th1 and Th2 cytokine production of splenocytes was assessed under stimulation with staphylococcal enterotoxin B (SEB) which induces a Th1 response in DS-Nh mice with or without TNCB sensitization. METHODS: We examined clinical skin changes, transepidermal water loss (TEWL), the number of S. aureus on the skin and the serum IgE levels in these mice treated repeatedly with TNCB under conventional conditions (free of fur mites). The splenocytes of DS-Nh mice were cultured with SEB and the cytokine levels in the supernatants were measured by enzyme-linked immunosorbent assay (ELISA). RESULTS: Significant skin changes were observed on the skin even where TNCB was not applied in both mice treated with TNCB. Increases in S. aureus on the skin and serum IgE levels were detected in DS-Nh mice, but not in NC/Nga mice. In DS-Nh mice, IFN-gamma and IL-13 production of splenocytes increased in the mice treated with TNCB. CONCLUSION: These results suggest that there might be a different mechanism of dermatitis induction between NC/Nga and DS-Nh mice. Th1 responses might play an important role in the development of dermatitis and increase in serum IgE levels in DS-Nh mice through an increase in IL-13 production.     

Serum and monoclonal immunoglobulin E antibodies from NC/Nga mice with severe atopic-like dermatitis recognize an auto-antigen, histone H3

Background NC/Nga mice are known to show a spontaneous outbreak of atopic‐like dermatitis accompanied by a marked elevation in serum IgE levels when reared in a conventional environment. The specific effects of such a strong serum IgE response on the development of the dermatitis and specific antigens recognized by the IgE antibodies are still uncertain. Objective and methods To characterize the IgE of NC/Nga mice, we established IgE‐secreting hybridoma clones from spleen cells of NC/Nga mice spontaneously developing dermatitis and identified variable‐region genes and specific antigens of the IgE monoclonal antibodies (mAbs). Serum polyclonal IgE, as well as IgG1 and IgG2a, specific for the identified antigen were also analysed. Results Four IgE‐producing hybridoma clones were established. Variable‐region nucleotide sequences of the IgE mAbs showed that these clones did not necessarily share common germline gene segments (V, D or J) for each variable region, and several somatic mutations had occured in the V gene segments. Through antigen screening, histone H3 was identified to be an auto‐antigen recognized by three of the four IgE mAbs. Serum IgE as well as IgG1 specific for histone H3 were almost undetectable in 6‐week‐old mice, but rapidly increased by 10–12 weeks of age. This age‐dependent increase in the serum anti‐histone H3 IgE was roughly in parallel with the onset of dermatitis, and slightly preceding total IgE elevation. The serum‐specific IgE level correlated well with a dermatitis‐severity score of each mouse at 12–16 weeks of age, and weakly with the severity of ear erosion of each mouse over 28 weeks of age. Furthermore, immunologically detectable histone‐H3 antigens were observed in skin tissue sections from the dermatitis sites. Conclusion In NC/Nga mice, anti‐histone H3 auto‐antibodies may contribute, at least in part, to the considerably elevated serum IgE and might play some roles in the development and exacerbation of dermatitis.     

A Role of Staphyococcus aureus, Interleukin-18, Nerve Growth Factor and Semaphorin 3A, an Axon Guidance Molecule, in Pathogenesis and Treatment of Atopic Dermatitis

Staphylococcus aureus (SA) is usually present not only in the skin lesions of atopic dermatitis (AD) but also in the atopic dry skin. SA discharges various toxins and enzymes that injure the skin, results in activation of epidermal keratinocytes, which produce and release IL-18. IL-18 that induces the super Th1 cells secreting IFN-γ and IL-13 is supposed to be involved in development of AD and its pathogenesis. Indeed, the number of SA colonies on the skin surface and the serum IL-18 levels in patients with AD significantly correlated with the skin scores of AD lesions. Also, there is strong positive correlation between the skin scores and serum IL-18 levels in DS-Nh mice (P<0.0001, r=0.64), which develop considerable AD-like legions when they are housed under conventional conditions, but develop skin legions with less severity and less frequency under specific pathogens free (SPF) conditions. Therefore, they are well-known as model mice of AD, in which SA is presumed to be critical factor for the development of AD lesions. Also, theses DS-Nh mice pretreated with Cy developed more remarkable AD-like lesions in comparison with non-treated ones. The levels of INF-r and IL-13 in the supernatants of the lymph node cell cultures stimulated with staphylococcal enterotoxin B (SEB) or ConA were increased in the Cy-treated mice, although the serum levels of total IgE were not. In this experiment, we revealed that Cy-treated mice, to which CD25 +CD4 + reguratory T cells taken from non-treated ones had been transferred, developed the AD-like legions with less severity and less number of SA colonies on the skin surface. Therefore, it is presumed that CD25 +CD4 + reguratory T cells might be involved in the suppression of super Th1 cells which are induced by IL-18 and are involved in the development of AD-like lesions rather than IgE production. The efficient induction of CD25 +CD4 + reguratory T cells is expected for the new type of treatment of AD. We also found that farnesol (F) and xylitol (X) synergistically inhibited biofilm formation by SA, and indeed the ratio of SA in total bacteria at sites to which the FX cream containing F and X had been applied was significantly decreased 1 week later, accompanied with improvement of AD, when compared with that before application and at placebo sites. Therefore, the FX cream is a useful skin-care agent for atopic dry skin colonized by SA. The nerve growth factor (NGF) in the horny layer (the horn NGF) of skin lesions on the cubital fossa was collected by tape stripping and measured using ELISA in AD patients before and after 2 and 4 weeks treatments. Simultaneously, the itch and eruptions on the whole body and on the lesions, in which the horn NGF was measured, were recorded, and also the peripheral blood eosinophil count, serum LDH level and serum total IgE level were examined. The level of NGF was significantly higher in AD patients than in healthy controls, correlated with the severity of itch, erythema, scale/xerosis, the eosinophil count and LDH level, and also significantly decreased after treatments with olopatadine and/or steroid ointment for 2 and 4 weeks. Therefore, the measurement of the NGF by this harmless method seems to be useful to assess the severity of AD and the therapeutic effects on AD. In AD patients, C-fiber in the epidermis increase and sprout, inducing hypersensitivity, which is considered to aggravate the disease. Semaphorin 3A (Sema3A), an axon guidance molecule, is a potent inhibitor of neurite outgrowth of sensory neurons. We administered recombinant Sema3A intracutaneously into the skin lesions of NC/Nga mice, an animal model of AD, and investigated the effect of Sema3A on the skin lesions and their itch. Sema3A dose-dependently improved skin lesions and attenuated the scratching behavior in NC/Nga mice. Histological examinations revealed a decrease in the epidermal thickness, the density of invasive nerve fibers in the epidermis, inflammatory infiltrate including mast cells and CD4 +T cells, and the production of IL-4 in the Sema3A-treated lesions. Because the interruption of the itch-scratch cycle likely contributes to the improvement of the AD-like lesions, Sema3A is expected to become a promising treatment of patients with refractory AD.     

Effect of Chrysanthemi borealis flos on atopic dermatitis induced by 1-chloro 2,4-dinitrobenzene in NC/Nga mouse

The flower of Chrysanthemum boreale has traditionally been used for treatment of various inflammatory disease including atopic dermatitis (AD). However, its action on AD is unclear. Therefore, we investigated the effect of CB on AD using NC/Nga mice as an AD model. The effect of CB on 1-Chloro-2,4-dinitrobenzene (DNCB) induced NC/Nga mice was evaluated by examining skin symptom severity, itching behavior, ear thickness, levels of serum Immunoglobulin E (IgE), tumor necrosis factor-α (TNF-α), and interleukin-4 (IL-4), skin histology. The CB significantly reduced the total clinical severity score, itching behavior, ear thickness and the level of serum IgE in AD mouse model. CB not only decreased TNF-α but also IL-4. These results suggest that CB may be a potential therapeutic modality for AD.     

Effect of the Hand Antiseptic Agents Benzalkonium Chloride,Povidone-Iodine,Ethanol, and Chlorhexidine Gluconate on Atopic Dermatitis in NC/Nga Mice

Antiseptic agents can cause skin irritation and lead to severe problems, especially for individuals with atopic diatheses. We investigated the effect of 4 different antiseptic agents using an atopic dermatitis (AD) model mouse. NC/Nga mice were subcutaneously injected with mite allergen (Dp) to induce AD-like skin lesions (ADSLs), and an application of 0.2% (w/v) benzalkonium chloride (BZK), 10% (w/v) povidone-iodine (PVP-I), 80% (v/v) ethanol (Et-OH), or 0.5% (v/v) chlorhexidine gluconate (CHG) was applied to the ear envelope. BZK induced a significant increase in the severity of the clinical score, infiltration of inflammatory cells, local expression of inflammatory cytokines in subcutaneous tissue, and total serum immunoglobulin (Ig) E. PVP-I increased the clinical score, number of mast cells, and production of inflammatory cytokines, and total serum IgE. Et-OH increased the clinical score and number of inflammatory cells, but showed no effect on serum IgE levels. No differences in any parameters were observed between CHG and the vehicle. Collectively, the results suggest the severity of the ADSL was related in part to the strength of the immunoreaction. These findings suggest that CHG could offer the lowest risk of inducing ADSL in individuals with atopic dermatitis and that medical staff and food handlers with AD could benefit from its use.     

Effect of Chrysanthemi borealis flos on atopic dermatitis induced by 1-chloro 2,4-dinitrobenzene in NC/Nga mouse

The flower of Chrysanthemum boreale has traditionally been used for treatment of various inflammatory disease including atopic dermatitis (AD). However, its action on AD is unclear. Therefore, we investigated the effect of CB on AD using NC/Nga mice as an AD model. The effect of CB on 1-Chloro-2,4-dinitrobenzene (DNCB) induced NC/Nga mice was evaluated by examining skin symptom severity, itching behavior, ear thickness, levels of serum Immunoglobulin E (IgE), tumor necrosis factor-α (TNF-α), and interleukin-4 (IL-4), skin histology. The CB significantly reduced the total clinical severity score, itching behavior, ear thickness and the level of serum IgE in AD mouse model. CB not only decreased TNF-α but also IL-4. These results suggest that CB may be a potential therapeutic modality for AD.     

Topical application of FK506 (tacrolimus) ointment inhibits mite antigen-induced dermatitis by local action in NC/Nga mice

BACKGROUND: FK506 ointment (tacrolimus ointment, protopic) is a new drug therapeutically effective for patients with atopic dermatitis (AD). However, the mechanism of action of FK506 ointment on AD is not fully understood. METHODS: We examined the effect of FK506 ointment on mite antigen-induced dermatitis in NC/Nga mice. Clinical symptoms and ear thickness were recorded, and histopathological studies and in vitro analyses were performed. RESULTS: Topical application of FK506 ointment (0.03-0.3%) suppressed the development of dermatitis. In the lesional skin, both interleukin (IL)-4 and interferon (IFN)-gamma were detected, even though the IL-4+/IFN-gamma- T helper 2 (Th2) population was predominant in the regional lymph nodes (LNs). Topical application of FK506 treatment reduced the elevated level of both IL-4 and IFN-gamma in the skin, but did not decrease the expansion of the Th2 population in the LNs. CONCLUSIONS: Topical application of FK506 ointment suppresses dermatitis by inhibiting the activation of inflammatory cells locally, without systemic immune suppression, in this AD model.     

Interleukin-18 is elevated in the sera from patients with atopic dermatitis and from atopic dermatitis model mice, NC/Nga

BACKGROUND: Several lines of in vitro and in vivo studies have demonstrated that interleukin-18 (IL-18) shows both antiallergic and allergy-promoting activities. But its expression in allergic diseases remains unknown. METHODS: Serum IL-18 levels from atopic dermatitis (AD) model mice, NC/Nga and control mice and from patients with AD and healthy volunteers were measured by ELISA. The relationship between IL-18 levels and serum IgE levels or clinical severity was also examined. RESULTS: Serum IL-18 levels from NC/Nga mice were significantly increased compared to those from control mice. The elevation of IL-18 in the sera was observed prior to the onset and during the development of dermatitis in NC/Nga mice. In addition, IL-18 levels in the sera from patients with AD were significantly (p < 0.05) elevated compared to those from healthy volunteers. However, serum IL-18 levels tended to correlate negatively with serum IgE levels in patients with AD and NC/Nga mice. CONCLUSION: IL-18 is overexpressed in AD.