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1.
Scand J Immunol ; 91(1): e12835, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31596502

RESUMO

Atopic dermatitis (AD) is a chronic and relapsing inflammatory skin disease. Molecular characterization of AD shows an underlying inflammation with tissue infiltration of T helper (TH ) 2 cells and increased IL-4 and IL-13. The multifaceted roles of IL-4 and IL-13 in allergic disease development make IL-4Rα an attractive target for treatment strategies, and a neutralizing monoclonal antibody which antagonizes the effects of both IL-4 and IL-13 by blocking the interaction site found in the IL-4 receptor subunit α (IL-4Rα) has been successfully used to treat patients with moderate-to-severe AD. To elucidate the effects of IL-4Rα blockade on the cellular level, we used flow cytometry to examine cytokine production after antigen stimulation in human T cells from patients with AD (n = 12) and healthy controls (n = 6). The cells were stimulated with and without a neutralizing monoclonal antibody against IL-4Rα. Our results indicate that blocking IL-4Rα prohibits IL-4 signalling and IL-13 signalling and thereby TH 2 differentiation followed by an upregulation of interferon-γ-producing cells.


Assuntos
Dermatite Atópica/imunologia , Dermatite Atópica/metabolismo , Subunidade alfa de Receptor de Interleucina-4/antagonistas & inibidores , Transdução de Sinais , Subpopulações de Linfócitos T/imunologia , Subpopulações de Linfócitos T/metabolismo , Células Th1/imunologia , Células Th1/metabolismo , Adulto , Biomarcadores , Citocinas/metabolismo , Feminino , Humanos , Imunoglobulina E/sangue , Imunoglobulina E/imunologia , Leucócitos Mononucleares/imunologia , Leucócitos Mononucleares/metabolismo , Masculino , Pessoa de Meia-Idade , Adulto Jovem
2.
Mol Med Rep ; 20(5): 4645-4653, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31545496

RESUMO

Previous studies have demonstrated that microRNA (miR)­146a is involved in the inflammatory response of atopic dermatitis (AD). The aim of the present study was to investigate the expression of miR­146a in the serum of patients with AD and in skin lesions of AD animal models. In addition, we aimed to predict and verify the target genes of miR­146a. miR­146a expression was measured in AD patient serum via reverse transcription­quantitative PCR. T­helper (Th)1 [CD4+; interferon (IFN)­Î³+] and Th2 [CD4+; interleukin (IL)­4+] expression in peripheral blood mononuclear cells was evaluated using flow cytometry. Following the establishment of a 2,4­dinitrofluorobenzene­induced C57BL/6 mouse AD model, Th1 (CD4+IFN­Î³+) and Th2 (CD4+IL­4+) expression was analyzed in murine spleen cells via flow cytometry. Plasmids were transfected into 293T cells and at 48 h post­transfection, cells were analyzed using a luciferase assay system. The results revealed that the AD group had a significantly lower Th1/Th2 ratio and a significantly higher miR­146a expression compared with the control group (P<0.05). Furthermore, a decreased Th1/Th2 ratio and a significantly increased miR­146a expression were observed in the model group compared with the control group (P<0.01). We also conducted a dual­luciferase assay to determine whether small ubiquitin­related modifier 1 (SUMO1) if the target gene of miR­146a. We observed a ~30% decrease in the relative luciferase activity in cells containing the 3'­untranslated region of SUMO1 + miR­146a). The results of the luciferase assay indicated that may be a direct mRNA target of miR­146a; however, the quantification of band density of SUMO1 expression following western blotting did not significantly differ. The development of animal models in AD research is of vital importance. The results revealed that miR­146a may be a potential regulator involved in the pathogenesis of AD. Furthermore, the current study determined that miR­146a could be a valuable marker of AD and thus, may be applied in the development of therapeutic strategies for treating AD.


Assuntos
Biomarcadores , Dermatite Atópica/etiologia , Regulação da Expressão Gênica , MicroRNAs/genética , Regiões 3' não Traduzidas , Adolescente , Adulto , Animais , Estudos de Casos e Controles , Criança , Pré-Escolar , Dermatite Atópica/metabolismo , Modelos Animais de Doenças , Suscetibilidade a Doenças , Feminino , Humanos , Leucócitos Mononucleares/metabolismo , Masculino , Camundongos , Interferência de RNA , Proteína SUMO-1/genética , Proteína SUMO-1/metabolismo , Baço/imunologia , Baço/metabolismo , Linfócitos T Auxiliares-Indutores/imunologia , Linfócitos T Auxiliares-Indutores/metabolismo , Adulto Jovem
3.
Nutrients ; 11(9)2019 Sep 05.
Artigo em Inglês | MEDLINE | ID: mdl-31492016

RESUMO

Soluble CD14 (sCD14) is one of the immunomodulatory factors in breast milk (BM). Although it may be involved in the prevention of atopic symptoms and sensitization to both food and inhalant allergens, conflicting evidence exists concerning its protective effects. In this study, we investigated the relationship between sCD14 in colostrum and 1-month BM, and the development of atopic dermatitis (AD) and sensitization to food and aeroallergens at 9 months of age in infants who were exclusively or almost exclusively breastfed up to 4 months of age. BM samples were collected from lactating mothers who participated in a 2 × 2 factorial, randomized, nontreatment controlled trial study set in Tokyo, which looked at the efficacy of emollients and synbiotics in preventing AD and food allergy in children during the first year of life. A total of 258 colostrum samples and 269 1-month BM samples were analyzed. We found that one-month BM sCD14 levels in the AD group were significantly lower than in the non-AD group. Levels of sCD14 in 1-month BM were not related to allergen sensitization in the overall analysis, but egg white sensitization correlated inversely with 1-month BM sCD14 in infants without AD. The results suggest that sCD14 in BM may be involved in atopic manifestations in early infancy.


Assuntos
Aleitamento Materno , Dermatite Atópica/prevenção & controle , Hipersensibilidade Alimentar/prevenção & controle , Receptores de Lipopolissacarídeos/imunologia , Leite Humano/imunologia , Adulto , Fatores Etários , Colostro/imunologia , Colostro/metabolismo , Dermatite Atópica/diagnóstico , Dermatite Atópica/imunologia , Dermatite Atópica/metabolismo , Feminino , Hipersensibilidade Alimentar/diagnóstico , Hipersensibilidade Alimentar/imunologia , Hipersensibilidade Alimentar/metabolismo , Humanos , Lactente , Receptores de Lipopolissacarídeos/metabolismo , Masculino , Leite Humano/metabolismo , Fatores de Proteção , Ensaios Clínicos Controlados Aleatórios como Assunto , Fatores de Risco , Tóquio
4.
Int J Mol Sci ; 20(17)2019 Aug 29.
Artigo em Inglês | MEDLINE | ID: mdl-31470652

RESUMO

Atopic dermatitis (AD) is the most common inflammatory skin disease worldwide. It is a chronic, relapsing and pruritic skin disorder which results from epidermal barrier abnormalities and immune dysregulation, both modulated by environmental factors. AD is strongly associated with asthma and allergic rhinitis in the so-called 'atopic march.' Xenobiotic receptors and their mates are ligand-activated transcription factors expressed in the skin where they control cellular detoxification pathways. Moreover, they regulate the expression of genes in pathways involved in AD in epithelial cells and immune cells. Activation or overexpression of xenobiotic receptors in the skin can be deleterious or beneficial, depending on context, ligand and activation duration. Moreover, their impact on skin might be amplified by crosstalk among xenobiotic receptors and their mates. Because they are activated by a broad range of endogenous molecules, drugs and pollutants owing to their promiscuous ligand affinity, they have recently crystalized the attention of researchers, including in dermatology and especially in the AD field. This review examines the putative roles of these receptors in AD by critically evaluating the conditions under which the proteins and their ligands have been studied. This information should provide new insights into AD pathogenesis and ways to develop new therapeutic interventions.


Assuntos
Dermatite Atópica/metabolismo , Receptores Citoplasmáticos e Nucleares/metabolismo , Pele/metabolismo , Xenobióticos/metabolismo , Asma/genética , Asma/imunologia , Asma/metabolismo , Dermatite Atópica/genética , Dermatite Atópica/imunologia , Eczema/genética , Eczema/imunologia , Eczema/metabolismo , Epiderme/imunologia , Epiderme/metabolismo , Epiderme/patologia , Regulação da Expressão Gênica/imunologia , Ligantes , Receptores Citoplasmáticos e Nucleares/genética , Rinite Alérgica/genética , Rinite Alérgica/imunologia , Rinite Alérgica/metabolismo , Pele/imunologia , Pele/patologia
5.
Chin J Nat Med ; 17(7): 525-534, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31514984

RESUMO

This study aimed to investigate the mechanisms of Yu-Ping-Feng-San (YPFS) on attenuating allergic inflammation in the initial stage of atopic dermatitis (AD). AD mouse model was established with fluorescein isothiocyanate (FITC) sensitization and elicitation. Epithelial barrier structure was observed with transmission electron microscope. The populations of dendritic cells (DCs) and group 2 innate lymphoid cells (ILC2s) were detected by flow cytometry. Human immortalized keratinocyte (HaCaT) cells were stimulated with Poly(I:C)/TNF-α in vitro to assessthymic stromal lymphopoietin (TSLP), interleukin (IL)-33 and nuclear factor-κB (NF-κB) levels or expressions by immunofluorescence, enzyme linked immunosorbent assay (ELISA) and western blot. In the initial stage of AD, ear swelling and infiltration of inflammatory cells in ear tissues were markedly attenuated with YPFS treatments. The damaged structures of ear epithelium and the increased levels of Th2-cytokines induced by FITC were significantly rescued in YPFS-treated mice. The production of pro-allergic cytokines, TSLP and IL-33, as well as the cell populations of their target cells DCs and ILC2s were decreased in AD model, respectively. Likewise, the levels of TSLP and IL-33 in Poly(I:C)/TNF-α-stimulated HaCaT cells showed the same results. Lower levels of p-NF-κB were detected with YPFS treatment, and the expressions of TSLP and IL-33 could be further decreased with inhibiting of NF-κB. Therefore, YPFS attenuates allergic inflammation in the initial stage of AD probably through regulating NF-κB-TSLP/IL-33 pathway, which may provide a novel effective target for the prevention and treatment of allergic diseases.


Assuntos
Antialérgicos/uso terapêutico , Citocinas/metabolismo , Dermatite Atópica/tratamento farmacológico , Medicamentos de Ervas Chinesas/uso terapêutico , Inflamação/prevenção & controle , Animais , Antialérgicos/farmacologia , Linhagem Celular , Células Dendríticas/patologia , Dermatite Atópica/induzido quimicamente , Dermatite Atópica/metabolismo , Modelos Animais de Doenças , Medicamentos de Ervas Chinesas/química , Medicamentos de Ervas Chinesas/farmacologia , Células Epiteliais/metabolismo , Fluoresceína-5-Isotiocianato/toxicidade , Inflamação/metabolismo , Inflamação/patologia , Queratinócitos/efeitos dos fármacos , Queratinócitos/metabolismo , Linfócitos/metabolismo , Linfócitos/patologia , Camundongos Endogâmicos BALB C , Extratos Vegetais/química , Extratos Vegetais/farmacologia , Extratos Vegetais/uso terapêutico
6.
Int J Mol Sci ; 20(16)2019 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-31443157

RESUMO

Active rebuilding, stabilizing, and maintaining the lipid barrier of the skin is an encouraging disease management and care concept for dry skin, atopic dermatitis (eczema, neurodermatitis), and psoriasis. For decades, corticosteroids have been the mainstay of topical therapy for atopic dermatitis; however, innovations within the scope of basic therapy are rare. In (extremely) dry, irritated, or inflammatory skin, as well as in lesions, an altered (sphingo)lipid profile is present. Recovery of a balanced (sphingo)lipid profile is a promising target for topical and personalized treatment and prophylaxis. New approaches for adults and small children are still lacking. With an ingenious combination of commonly used active ingredients, it is possible to restore and reinforce the dermal lipid barrier and maintain refractivity. Lysosomes and ceramide de novo synthesis play a key role in attenuation of the dermal lipid barrier. Linoleic acid in combination with amitriptyline in topical medication offers the possibility to relieve patients affected by dry and itchy skin, mild to moderate atopic dermatitis lesions, and eczemas without the commonly occurring serious adverse effects of topical corticosteroids or systemic antibody administration.


Assuntos
Ceramidas/metabolismo , Dermatite Atópica/metabolismo , Amitriptilina/uso terapêutico , Animais , Antioxidantes/metabolismo , Apoptose/fisiologia , Humanos , Ácido Linoleico/uso terapêutico , Esfingolipídeos/metabolismo
7.
Int J Mol Sci ; 20(16)2019 Aug 20.
Artigo em Inglês | MEDLINE | ID: mdl-31434203

RESUMO

Severe pruritus is a characteristic feature of atopic dermatitis (AD) and is closely related to its activity. Recent studies have shown that IL-31 is a key determinant of pruritus in AD. Anti-IL-31 receptor alpha (IL-31RA) antibody treatment has also been reported to improve pruritus clinically, subsequently contributing to the attenuation of AD disease activity. Therefore, IL-31 has been thought to be an important cytokine for regulating pruritus and AD disease activity; however, how IL-31 is involved in the immune response in AD has remained largely unknown. Epidermal Langerhans cells (LCs) and dermal dendritic cells (DCs) derived from bone marrow cells have been reported to play a critical role in AD pathogenesis. LCs and DCs produce Ccl 17 and Ccl 22, which chemoattract Th2 cells, leading to AD development. Therefore, we aimed to clarify how IL-31/IL-31RA interaction affects Ccl 17 and Ccl 22 production. To test this, we analyzed murine bone marrow-derived DCs (BMDCs) stimulated with IL-4, an important cytokine in AD development. We found that IL-31RA expression was upregulated by IL-4 stimulation in a dose-dependent manner in BMDCs. Furthermore, IL-31 upregulates Ccl 17 and Ccl 22 production in the presence of IL-4, whereas IL-31 stimulation alone did not produce Ccl 17 and Ccl 22. These findings suggest that IL-4 mediates IL-31RA expression and IL-31/IL-31RA interaction augments Ccl 17 and Ccl 22 production in BMDCs, which promotes Th2-deviated immune response in AD. Since we previously reported that soybean tar Glyteer, an aryl hydrocarbon receptor (AHR) ligand, impairs IL-4/Stat 6 signaling in BMDCs, we examined whether Glyteer affects IL-31RA expression induced by IL-4 stimulation. Glyteer inhibited upregulation of IL-31RA expression induced by IL-4 stimulation in a dose-dependent manner. Glyteer also inhibited Ccl 17 and Ccl 22 production induced by IL-4 and IL-31 stimulation. Taken together, these findings suggest that Glyteer treatment may improve AD disease activity by impairing IL-31/IL-31RA interaction in DCs.


Assuntos
Células Dendríticas/metabolismo , Dermatite Atópica/metabolismo , Interleucina-4/farmacologia , Interleucinas/metabolismo , Receptores de Interleucina/metabolismo , Animais , Células Dendríticas/efeitos dos fármacos , Dermatite Atópica/tratamento farmacológico , Ensaio de Imunoadsorção Enzimática , Citometria de Fluxo , Interleucina-4/uso terapêutico , Camundongos Endogâmicos C57BL , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Transdução de Sinais/efeitos dos fármacos
8.
Int J Mol Sci ; 20(17)2019 Aug 21.
Artigo em Inglês | MEDLINE | ID: mdl-31438472

RESUMO

Atopic dermatitis (AD) is the most common chronic and relapsing inflammatory skin disease. AD is typically characterized by skewed T helper (Th) 2 inflammation, yet other inflammatory profiles (Th1, Th17, Th22) have been observed in human patients. How cytokines from these different Th subsets impact barrier function in this disease is not well understood. As such, we investigated the impact of the canonical Th17 cytokine, IL-17A, on barrier function and protein composition in primary human keratinocytes and human skin explants. These studies demonstrated that IL-17A enhanced tight junction formation and function in both systems, with a dependence on STAT3 signaling. Importantly, the Th2 cytokine, IL-4 inhibited the barrier-enhancing effect of IL-17A treatment. These observations propose that IL-17A helps to restore skin barrier function, but this action is antagonized by Th2 cytokines. This suggests that restoration of IL-17/IL-4 ratio in the skin of AD patients may improve barrier function and in so doing improve disease severity.


Assuntos
Epiderme/efeitos dos fármacos , Epiderme/metabolismo , Interleucina-17/farmacologia , Interleucina-4/farmacologia , Junções Íntimas/efeitos dos fármacos , Junções Íntimas/metabolismo , Células Cultivadas , Claudina-4/metabolismo , Dermatite Atópica/metabolismo , Humanos , Técnicas In Vitro , Queratinócitos/efeitos dos fármacos , Queratinócitos/metabolismo , Fator de Transcrição STAT3/metabolismo , Pele/efeitos dos fármacos , Pele/metabolismo
9.
Nutrients ; 11(7)2019 Jun 30.
Artigo em Inglês | MEDLINE | ID: mdl-31262028

RESUMO

Raw cow's milk was previously shown to suppress allergic symptoms in a murine model for food allergy. In the present study, we investigated the contribution of fat content and heat-sensitive milk components to this allergy-protective effect. In addition, we determined the potency of alkaline phosphatase (ALP), a heat-sensitive raw milk component, to affect the allergic response. C3H/HeOuJ mice were treated with raw milk, pasteurized milk, skimmed raw milk, pasteurized milk spiked with ALP, or phosphate-buffered saline for eight days prior to sensitization and challenge with ovalbumin (OVA). Effects of these milk types on the allergic response were subsequently assessed. Similar to raw milk, skimmed raw milk suppressed food allergic symptoms, demonstrated by a reduced acute allergic skin response and low levels of OVA-specific IgE and Th2-related cytokines. This protective effect was accompanied by an induction of CD103+CD11b+ dendritic cells and TGF-ß-producing regulatory T cells in the mesenteric lymph nodes. Pasteurized milk was not protective but adding ALP restored the allergy-protective effect. Not the fat content, but the heat-sensitive components are responsible for the allergy-protective effects of raw cow's milk. Adding ALP to heat-treated milk might be an interesting alternative to raw cow's milk consumption, as spiking pasteurized milk with ALP restored the protective effects.


Assuntos
Fosfatase Alcalina/imunologia , Dermatite Atópica/prevenção & controle , Manipulação de Alimentos/métodos , Hipersensibilidade Alimentar/prevenção & controle , Proteínas do Leite/imunologia , Pasteurização , Animais , Basófilos/imunologia , Basófilos/metabolismo , Células Cultivadas , Citocinas/metabolismo , Dermatite Atópica/imunologia , Dermatite Atópica/metabolismo , Modelos Animais de Doenças , Feminino , Hipersensibilidade Alimentar/imunologia , Hipersensibilidade Alimentar/metabolismo , Imunoglobulinas/sangue , Lipídeos/imunologia , Linfonodos/imunologia , Linfonodos/metabolismo , Camundongos Endogâmicos C3H , Ovalbumina , Desnaturação Proteica , Pele/imunologia , Pele/metabolismo , Baço/imunologia , Baço/metabolismo
10.
Mol Pharmacol ; 96(3): 393-400, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31308264

RESUMO

Atopic dermatitis (AD) is a chronic inflammatory skin disease characterized by cutaneous lesions and intense pruritus. The warm temperature-activated Ca2+-permeable transient receptor potential vanilloid (TRPV)3 channel is abundantly expressed in keratinocytes, and gain-of-function mutations of TRPV3 cause skin lesions and pruritus in rodents and humans, suggesting an involvement of TRPV3 in the pathogenesis of AD. Here we report that pharmacological and genetic inhibition of TRPV3 attenuates skin lesions and dermatitis in mice. We found that TRPV3 proteins, together with inflammatory factors tumor necrosis factor (TNF)-α and interleukin (IL)-6, were upregulated in the skin of mice in a AD-like model induced by topical application of chemical 2,4-dinitrofluorobenzene, as detected by Western blot analysis and immunostaining assays. Pharmacological activation of TRPV3 by channel agonist and skin sensitizer carvacrol resulted in the development of AD in wild-type mice but not in TRPV3 knockout mice. Furthermore, inhibition of TRPV3 by natural osthole reversed the severity of inflammatory dorsal skin and ear edema in a dose-dependent manner and also decreased expression of inflammatory factors TNF-α and IL-6. Taken together, our findings demonstrate the involvement of overactive TRPV3 in the progressive pathology of AD in mice, and topical inhibition of TRPV3 channel function may represent an effective option for preventing and treating AD or inflammatory skin diseases. SIGNIFICANCE STATEMENT: The overactive transient receptor potential vanilloid TRPV3 channel is critically involved in the pathogenesis of atopic dermatitis. Inhibition of TRPV3 channel function by topical natural osthole may represent an effective therapy for management of atopic dermatitis aimed at preventing or alleviating skin lesions and severe itching.


Assuntos
Cumarínicos/administração & dosagem , Dermatite Atópica/metabolismo , Dinitrofluorbenzeno/efeitos adversos , Canais de Cátion TRPV/metabolismo , Administração Tópica , Animais , Cumarínicos/farmacologia , Dermatite Atópica/induzido quimicamente , Dermatite Atópica/tratamento farmacológico , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Temperatura Alta , Humanos , Interleucina-6/metabolismo , Masculino , Camundongos , Fator de Necrose Tumoral alfa/metabolismo , Regulação para Cima/efeitos dos fármacos
11.
Medicine (Baltimore) ; 98(29): e16527, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31335732

RESUMO

INTRODUCTION: Several studies have found that obesity is associated with atopic dermatitis (AD); however, the mechanisms underlying the association are largely unknown. This study aims to assess the association of AD with obesity in the Korean population and verify its mechanism via a multi-omics analysis. METHODS AND ANALYSIS: A case-control study will be conducted in the Republic of Korea. A total of 80 subjects, aged 4 to 12 years, matched for age and sex, with body mass index at or above the 85th percentile or at or below the 25th percentile, will be included. Subjects will be assigned to the following 4 groups: obese/overweight with AD, normal/underweight with AD, obese/overweight control, and normal/underweight control. Serum metabolome and immune biomarkers, as well as fecal metabolome and microbiome biomarkers, will be analyzed. Serum eosinophil cationic protein, total serum Immunoglobulin E (IgE), and specific IgE will be analyzed to assess allergic tendency. The SCORing of AD index, the children's dermatology life quality index, body composition analysis, and the Korean gastrointestinal symptom rating scale will be obtained to assess the disease status and severity of the subjects. DISCUSSION: The findings of this study are expected to provide evidence of an association between AD and obesity via a gut microbiome-metabolome-immune mechanism. Therefore, it may improve future management strategies for AD. TRIAL REGISTRATION: This study has been registered at the Korean National Clinical Trial Registry, Clinical Research Information Service (KCT0003630).


Assuntos
Dermatite Atópica/complicações , Dermatite Atópica/metabolismo , Obesidade/complicações , Obesidade/metabolismo , Biomarcadores/sangue , Índice de Massa Corporal , Estudos de Casos e Controles , Criança , Pré-Escolar , Dermatite Atópica/imunologia , Dermatite Atópica/microbiologia , Proteína Catiônica de Eosinófilo/sangue , Fezes/química , Fezes/microbiologia , Feminino , Microbioma Gastrointestinal , Humanos , Imunoglobulina E/sangue , Masculino , Metaboloma , Obesidade/imunologia , Obesidade/microbiologia , Qualidade de Vida , República da Coreia
12.
Vet Dermatol ; 30(5): 383-e114, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31218782

RESUMO

BACKGROUND: The pathogenesis of canine atopic dermatitis (AD) is complex. Dysregulation of the cutaneous immune system is considered an important regulator of the allergic response. Exploration of association of interleukin-17 (IL-17), IL-31, IgE and leukogram attributes with canine AD could provide novel insights into its immunopathology. HYPOTHESIS/OBJECTIVES: To investigate possible associations of IL-17, IL-3, IgE and leukogram attributes of canine AD. ANIMALS: 17 dogs diagnosed with AD and six healthy dogs. METHODS AND MATERIALS: Circulating concentrations of IL-17, IL-31 and total IgE from sera samples were determined using commercial canine-specific quantitative immunoassay kits. Complete blood cell counts were analysed by an automated haematology analyser. Statistical differences between the two groups were determined using an unpaired t-test. The degree of relationship between the IL-17, IL-31, IgE, total leukocyte count (TLC) values and clinical signs scores (Canine Atopic Dermatitis Lesion Index and pruritus Visual Analog Scale pVAS) was determined by Pearson's r correlation statistic. RESULTS: Dogs with AD had significantly (P < 0.0001) higher circulating concentrations of IL-17, IL-31 and total IgE compared with healthy dogs. Dogs with AD also had significantly higher TLC (P < 0.0002), absolute neutrophils (P < 0.0001) and absolute eosinophils (P < 0.0001) counts, and percentage of neutrophils (P < 0.03) and eosinophils (P < 0.0001) compared with healthy controls. A significant positive correlation (r2  = 0.396; P < 0.007) between the pVAS and IL-31 was observed in dogs with AD. CONCLUSIONS AND CLINICAL IMPORTANCE: Marked elevation in circulating IL-17, IL-31 and total IgE along with the abnormalities in leukogram may be associated with canine AD and could be possible targets in the therapeutic management of canine AD.


Assuntos
Dermatite Atópica/veterinária , Doenças do Cão/metabolismo , Imunoglobulina E/sangue , Interleucinas/metabolismo , Animais , Estudos de Casos e Controles , Dermatite Atópica/sangue , Dermatite Atópica/metabolismo , Cães , Interleucinas/sangue , Interleucinas/genética
13.
Biochem Med (Zagreb) ; 29(2): 020501, 2019 Jun 15.
Artigo em Inglês | MEDLINE | ID: mdl-31223255

RESUMO

There is an increasing number of experimental, genetic and clinical evidence of atopic dermatitis expression as a pre-condition for later development of other atopic diseases such as asthma, food allergy and allergic rhinitis. Atopic dermatitis is a heterogeneous, recurrent childhood disease, also present in the adult age. It is increasingly attributed to systemic features and is characterized by immunological and skin barrier integrity and function dysregulation. To maintain the protective function of the skin barrier, in particular the maintenance of pH, hydration and antimicrobial functions, the filaggrin, among others, plays a significant role. Filaggrin is a multifunctional, histidine-rich, insoluble protein. The lack of filaggrin is associated with various cutaneous (e.g. ichthyosis vulgaris, allergic contact dermatitis) and non-cutaneous (e.g. diabetes, inflammatory conditions of the gastrointestinal tract) diseases and may be a result of genetic, immunological factors combined with environmental factors. In this review we summarised (emphasized) recent findings in understanding the role of filaggrin in atopic dermatitis and other diseases, participants in the atopic march.


Assuntos
Dermatite Atópica , Proteínas de Filamentos Intermediários , Dermatite Atópica/diagnóstico , Dermatite Atópica/genética , Dermatite Atópica/metabolismo , Humanos , Proteínas de Filamentos Intermediários/análise , Proteínas de Filamentos Intermediários/genética , Proteínas de Filamentos Intermediários/metabolismo
14.
J Hum Genet ; 64(9): 911-917, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31249362

RESUMO

Atopic dermatitis (AD) is a chronic inflammatory skin disease, and skin barrier defects are often observed in patients with AD. So far, few association studies between FLG loss-of-function mutations and onset of AD in longitudinal studies of early childhood have been reported. In the present study, we aimed to investigate the effect of FLG loss-of-function mutations on the development of AD in a longitudinal birth cohort study. The status of AD diagnosis at each age until 6 years was collected from the Tokyo Children's Health, Illness, and Development (T-CHILD) study. We analyzed eight loss-of-function mutations in FLG in 712 participants. FLG loss-of-function mutations were significantly associated with AD onset in infancy (≤2 years) (P < 0.001, OR 3.54, 95% CI 1.88-6.65), but not with AD onset in childhood (≥3 years) (P = 0.981, OR 0.99, 95% CI 0.29-3.36), and none of the children in the present cohort who developed AD at 5 years of age or later carried FLG loss-of-function mutations. Our data support the notion that the effect of FLG loss-of-function mutations is prominent during a very early stage of life.


Assuntos
Dermatite Atópica , Mutação com Perda de Função , Proteínas S100/genética , Criança , Pré-Escolar , Dermatite Atópica/genética , Dermatite Atópica/metabolismo , Dermatite Atópica/patologia , Feminino , Seguimentos , Humanos , Lactente , Estudos Longitudinais , Masculino , Proteínas S100/metabolismo
15.
Cells ; 8(5)2019 05 22.
Artigo em Inglês | MEDLINE | ID: mdl-31121896

RESUMO

Atopic dermatitis (AD) is characterized by dry and itchy skin evolving into disseminated skin lesions. AD is believed to result from a primary acquired or a genetically-induced epidermal barrier defect leading to immune hyper-responsiveness. Filaggrin (FLG) is a protein found in the cornified envelope of fully differentiated keratinocytes, referred to as corneocytes. Although FLG null mutations are strongly associated with AD, they are not sufficient to induce the disease. Moreover, most patients with ichthyosis vulgaris (IV), a monogenetic skin disease characterized by FLG homozygous, heterozygous, or compound heterozygous null mutations, display non-inflamed dry and scaly skin. Thus, all causes of epidermal barrier impairment in AD have not yet been identified, including those leading to the Th2-predominant inflammation observed in AD. Three dimensional organotypic cultures have emerged as valuable tools in skin research, replacing animal experimentation in many cases and precluding the need for repeated patient biopsies. Here, we review the results on IV and AD obtained with epidermal or skin equivalents and consider these findings in the context of human in vivo data. Further research utilizing complex models including immune cells and cutaneous innervation will enable finer dissection of the pathogenesis of AD and deepen our knowledge of epidermal biology.


Assuntos
Dermatite Atópica/patologia , Ictiose Vulgar/patologia , Proteínas de Filamentos Intermediários/genética , Proteínas de Filamentos Intermediários/metabolismo , Células Cultivadas , Dermatite Atópica/metabolismo , Humanos , Hipersensibilidade/metabolismo , Ictiose Vulgar/metabolismo , Inflamação/metabolismo , Modelos Biológicos , Mutação , Pele/metabolismo , Pele/patologia
16.
Int J Mol Sci ; 20(10)2019 May 20.
Artigo em Inglês | MEDLINE | ID: mdl-31137528

RESUMO

Atopic dermatitis (AD) is a recurrent allergic skin disease caused by genetic and environmental factors. Patients with AD may experience immune imbalance, increased levels of mast cells, immunoglobulin (Ig) E and pro-inflammatory factors (Cyclooxygenase, COX-2 and inducible NO synthase, iNOS). While spilanthol (SP) has anti-inflammatory and analgesic activities, its effect on AD remains to be explored. To develop a new means of SP, inflammation-related symptoms of AD were alleviated, and 2,4-dinitrochlorobenzene (DNCB) was used to induce AD-like skin lesions in BALB/c mice. Histopathological analysis was used to examine mast cells and eosinophils infiltration in AD-like skin lesions. The levels of IgE, IgG1 and IgG2a were measured by enzyme-linked immunosorbent assay (ELISA) kits. Western blot was used for analysis of the mitogen-activated protein kinase (MAPK) pathways and COX-2 and iNOS protein expression. Topical SP treatment reduced serum IgE and IgG2a levels and suppressed COX-2 and iNOS expression via blocked mitogen-activated protein kinase (MAPK) pathways in DNCB-induced AD-like lesions. Histopathological examination revealed that SP reduced epidermal thickness and collagen accumulation and inhibited mast cells and eosinophils infiltration into the AD-like lesions skin. These results indicate that SP may protect against AD skin lesions through inhibited MAPK signaling pathways and may diminish the infiltration of inflammatory cells to block allergic inflammation.


Assuntos
Antialérgicos/uso terapêutico , Anti-Inflamatórios/uso terapêutico , Dermatite Atópica/tratamento farmacológico , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Alcamidas Poli-Insaturadas/uso terapêutico , Animais , Antialérgicos/administração & dosagem , Antialérgicos/farmacologia , Anti-Inflamatórios/administração & dosagem , Anti-Inflamatórios/farmacologia , Ciclo-Oxigenase 2/genética , Ciclo-Oxigenase 2/metabolismo , Dermatite Atópica/etiologia , Dermatite Atópica/metabolismo , Dinitroclorobenzeno/toxicidade , Feminino , Imunoglobulinas/genética , Imunoglobulinas/metabolismo , Camundongos , Camundongos Endogâmicos BALB C , Óxido Nítrico Sintase Tipo II/genética , Óxido Nítrico Sintase Tipo II/metabolismo , Alcamidas Poli-Insaturadas/administração & dosagem , Alcamidas Poli-Insaturadas/farmacologia
17.
Biofactors ; 45(4): 536-547, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31087730

RESUMO

The effects of environmental insults on human health are a major global concern. Some of the most noxious pollutants that humans are exposed to include ozone (O3 ), particulate matter (PM), and cigarette smoke (CS). Since the skin is the first line of defense against environmental insults, it is considered one of the main target organs for the harmful insults of air pollution. Thus, there is solid evidence that skin pathologies such as premature aging, atopic dermatitis (AD), and psoriasis are associated with pollutant exposure; all of these skin conditions are also associated with an altered redox status. Therefore, although the mechanisms of action and concentrations of O3 , PM, and CS that we are exposed to differ, exposure to all of these pollutants is associated with the development of similar skin conditions due to the fact that all of these pollutants alter redox homeostasis, increasing reactive oxygen species production and oxidative stress. A main product of oxidative stress, induced by exposure to the aforementioned pollutants, is 4-hydroxy-2-nonenal (HNE), which derives from the oxidation of ω-6 polyunsaturated fatty acids. HNE is a highly reactive compound that can form adducts with cellular proteins and even DNA; it is also an efficient cell signaling molecule able to regulate mitogen-activated protein kinase pathways and the activity of redox-sensitive transcription factors such as Nrf2, AP1, and NFκB. Therefore, increased levels of HNE in the skin, in response to pollutants, likely accelerates skin aging and exacerbates existing skin inflammatory conditions; thus, targeting HNE formation could be an innovative cosmeceutical approach for topical applications.


Assuntos
Poluentes Atmosféricos/toxicidade , Aldeídos/toxicidade , Dermatite Atópica/induzido quimicamente , Material Particulado/toxicidade , Psoríase/induzido quimicamente , Envelhecimento da Pele/efeitos dos fármacos , Pele/efeitos dos fármacos , Poluentes Atmosféricos/metabolismo , Aldeídos/metabolismo , Dermatite Atópica/genética , Dermatite Atópica/metabolismo , Dermatite Atópica/patologia , Regulação da Expressão Gênica/efeitos dos fármacos , Humanos , Proteínas Quinases Ativadas por Mitógeno/genética , Proteínas Quinases Ativadas por Mitógeno/metabolismo , Oxirredução , Estresse Oxidativo , Ozônio/metabolismo , Ozônio/toxicidade , Psoríase/genética , Psoríase/metabolismo , Psoríase/patologia , Espécies Reativas de Oxigênio/agonistas , Espécies Reativas de Oxigênio/metabolismo , Transdução de Sinais , Pele/metabolismo , Pele/patologia , Envelhecimento da Pele/genética , Envelhecimento da Pele/patologia , Poluição por Fumaça de Tabaco/efeitos adversos , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo
18.
Toxins (Basel) ; 11(5)2019 04 26.
Artigo em Inglês | MEDLINE | ID: mdl-31027358

RESUMO

Bee venom (BV)-a complex mixture of peptides and toxic proteins including phospholipase A2 and melittin-promotes blood clotting. In this study, we investigated the anti-atopic properties of BV and the mechanism associated with its regulation of the complement system. BV treatment upregulated the mRNA and protein levels of CD55 in THP-1 cells. Further experiments revealed that the phosphorylation of ERK was associated with upregulation of CD55. A complement-dependent cytotoxicity assay and a bacteria-killing assay showed that BV inactivated the complement system through the induction of CD55. The serum levels of C3 convertase (C3C) and Membrane attack complex (MAC) increased, while CD55 decreased in mice with AD-like lesions from DNCB treatment. However, the levels were inverted when the AD-like mice were treated with BV using subcutaneous injection, and we observed that the AD symptoms were alleviated. BV is often used to treat AD but its mechanism has not been elucidated. Here, we suggest that BV alleviates AD through the inactivation of the complement system, especially by the induction of CD55.


Assuntos
Anti-Inflamatórios/uso terapêutico , Venenos de Abelha/uso terapêutico , Antígenos CD55/metabolismo , Dermatite Atópica/tratamento farmacológico , Animais , Anti-Inflamatórios/farmacologia , Venenos de Abelha/farmacologia , Antígenos CD55/genética , Linhagem Celular , Convertases de Complemento C3-C5/metabolismo , Complexo de Ataque à Membrana do Sistema Complemento/metabolismo , Dermatite Atópica/genética , Dermatite Atópica/metabolismo , Escherichia coli/efeitos dos fármacos , Humanos , Masculino , Camundongos Endogâmicos BALB C , Proteínas Quinases Ativadas por Mitógeno/metabolismo , Regulação para Cima/efeitos dos fármacos
19.
Int Immunopharmacol ; 72: 62-73, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-30959373

RESUMO

This study evaluated the role of kinin B1 and B2 receptors in the pre-clinical mouse model of oxazolone-induced atopic dermatitis. The B1 R715 or B2 HOE140 receptor antagonists were dosed at different schemes of treatment. After assessment of clinical lesion scores and pruritus, lesional skin samples were collected for histopathological analysis. The plasma extravasation and the expression of the metalloproteinase ADAMTS5 were also assessed. The immunopositivity for kinin receptors was evaluated in the skin, dorsal root ganglion (DRG), thoracic spinal cord and brain cortex sections. Marked upregulation of B1 and B2 receptors was observed in the skin of oxazolone-treated mice. The induction of atopic dermatitis led to a downregulation of both receptors in the DRG, without any alteration in the spinal cord and brain cortex. The repeated administration of HOE140 (50 nmol/kg; i.p.) partially inhibited the oxazolone-related pruritus, associated with a reduction of ADAMTS5 immunolabelling in the skin. Alternatively, R715 (438 nmol/kg; i.p.) produced a mild inhibition of plasma extravasation in oxazolone-challenged mice. Noteworthy, the repeated i.d. injection of R715 (30 nmol/site) or HOE140 (3 nmol/site) significantly reduced the histiocyte numbers, according to the histopathological analysis. Either B1 or B2 kinin antagonists, irrespective of the protocol of treatment, did not alter any other evaluated clinical or histological parameters. Data brings novel evidence about the role of kinin receptors in allergy-related conditions, such as atopic dermatitis. Further studies to test different protocols of treatment with kinin antagonists on in-depth cellular alterations underlying oxazolone-induced atopic dermatitis remain to be performed.


Assuntos
Dermatite Atópica/imunologia , Receptor B1 da Bradicinina/imunologia , Receptor B2 da Bradicinina/imunologia , Animais , Córtex Cerebral/metabolismo , Dermatite Atópica/induzido quimicamente , Dermatite Atópica/metabolismo , Modelos Animais de Doenças , Gânglios Espinais/metabolismo , Masculino , Camundongos , Oxazolona , Receptor B1 da Bradicinina/metabolismo , Receptor B2 da Bradicinina/metabolismo , Medula Espinal/metabolismo
20.
Molecules ; 24(8)2019 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-30991764

RESUMO

Physcion is well known for the treatment of carcinoma. However, the therapeutic effect of physcion on atopic dermatitis (AD) through the inhibition of thymic stromal lymphopoietin (TSLP) level remains largely unknown. In this study, we investigated the anti-AD effect of physcion using HMC-1 cells, splenocytes, and a murine model. Treatment with physcion decreased production and mRNA expression levels of TSLP, IL-6, TNF-ɑ, and IL-1ß in activated HMC-1 cells. Physcion reduced the expression levels of RIP2/caspase-1 and phospho (p)ERK/pJNK/pp38 in activated HMC-1 cells. Physcion suppressed the expression levels of pIKKß/NF-κB/pIkB in activated HMC-1 cells. Moreover, physcion attenuated the production levels of TSLP, IL-4, IL-6, TNF-, and IFN-γ from activated splenocytes. Oral administration of physcion improved the severity of 2,4-dinitrochlorobenzene-induced AD-like lesional skin through reducing infiltration of inflammatory cells and mast cells, and the protein and mRNA levels of TSLP, IL-4, and IL-6 in the lesional skin tissues. Physcion attenuated histamine, IgE, TSLP, IL-4, IL-6, and TNF- levels in serum. In addition, physcion inhibited caspase-1 activation in the lesional skin tissues. These findings indicate that physcion could ameliorate AD-like skin lesions by inhibiting TSLP levels via caspase-1/MAPKs/NF-kB signalings, which would provide experimental evidence of the therapeutic potential of physcion for AD.


Assuntos
Citocinas/metabolismo , Dermatite Atópica/tratamento farmacológico , Dermatite Atópica/metabolismo , Emodina/análogos & derivados , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Animais , Caspase 1/metabolismo , Dermatite Atópica/induzido quimicamente , Dermatite Atópica/patologia , Dinitrofluorbenzeno/toxicidade , Emodina/farmacologia , Histamina/metabolismo , Humanos , Mastócitos/metabolismo , Mastócitos/patologia , Camundongos , NF-kappa B/metabolismo
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