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1.
Int J Mol Sci ; 21(22)2020 Nov 13.
Artigo em Inglês | MEDLINE | ID: mdl-33202847

RESUMO

Emerging evidence has demonstrated that Toll-like receptors (TLRs) are associated with autoimmune diseases. In this study, we investigated the role of TLR2 in psoriasis using imiquimod-induced psoriasis-like dermatitis. Although TLR2 signaling is known to play a critical role in the induction of proinflammatory cytokines by immune cells, such as dendritic cells (DCs), macrophages, and monocytes, TLR2 deficiency unexpectedly exacerbated psoriasiform skin inflammation. Importantly, messenger RNA (mRNA) levels of Foxp-3 and IL-10 in the lesional skin were significantly decreased in TLR2 KO mice compared with wild-type mice. Furthermore, flow cytometric analysis of the lymph nodes revealed that the frequency of regulatory T cells (Tregs) among CD4-positive cells was decreased. Notably, stimulation with Pam3CSK4 (TLR2/1 ligand) or Pam2CSK4 (TLR2/6 ligand) increased IL-10 production from Tregs and DCs and the proliferation of Tregs. Finally, adoptive transfer of Tregs from wild-type mice reduced imiquimod-induced skin inflammation in TLR2 KO mice. Taken together, our results suggest that TLR2 signaling directly enhances Treg proliferation and IL-10 production by Tregs and DCs, suppressing imiquimod-induced psoriasis-like skin inflammation. Enhancement of TLR2 signaling may be a new therapeutic strategy for psoriasis.


Assuntos
Imiquimode/efeitos adversos , Interleucina-10 , Psoríase , Pele , Linfócitos T Reguladores , Receptor 2 Toll-Like/deficiência , Animais , Imiquimode/farmacologia , Inflamação/induzido quimicamente , Inflamação/genética , Inflamação/imunologia , Inflamação/patologia , Interleucina-10/genética , Interleucina-10/imunologia , Camundongos , Camundongos Knockout , Psoríase/induzido quimicamente , Psoríase/genética , Psoríase/imunologia , Psoríase/patologia , Pele/imunologia , Pele/patologia , Linfócitos T Reguladores/imunologia , Linfócitos T Reguladores/patologia , Receptor 2 Toll-Like/imunologia
2.
Int J Mol Sci ; 21(10)2020 May 23.
Artigo em Inglês | MEDLINE | ID: mdl-32456211

RESUMO

Interferon regulatory factors (IRFs) play diverse roles in the regulation of the innate and adaptive immune responses in various diseases. In psoriasis, IRF2 is known to be involved in pathogenesis, while studies on other IRFs are limited. In this study, we investigated the role of IRF5 in psoriasis using imiquimod-induced psoriasis-like dermatitis. Although IRF5 is known to play a critical role in the induction of proinflammatory cytokines by immune cells, such as dendritic cells (DCs), macrophages, and monocytes, IRF5 deficiency unexpectedly exacerbated psoriasiform skin inflammation. The interferon-α and tumor necrosis factor-α mRNA expression levels were decreased, while levels of Th17 cytokines including IL-17, IL-22, and IL-23 were increased in IRF5-deficient mice. Furthermore, IL-23 expression in DCs from IRF5-deficient mice was upregulated both in steady state and after toll-like receptor 7/8 agonist stimulation. Importantly, the expression of IRF4, which is also important for the IL-23 production in DCs, was augmented in DCs from IRF5-deficient mice. Taken together, our results suggest that IRF5 deficiency induces the upregulation of IRF4 in DCs followed by augmented IL-23 production, resulting in the amplification of Th17 responses and the exacerbation of imiquimod-induced psoriasis-like skin inflammation. The regulation of IRF4 or IRF5 expression may be a novel therapeutic approach to psoriasis.


Assuntos
Fatores Reguladores de Interferon/genética , Interleucinas/metabolismo , Psoríase/metabolismo , Animais , Células Cultivadas , Células Dendríticas/metabolismo , Feminino , Imiquimode/toxicidade , Indutores de Interferon/toxicidade , Fatores Reguladores de Interferon/deficiência , Fatores Reguladores de Interferon/metabolismo , Interferons/genética , Interferons/metabolismo , Interleucinas/genética , Macrófagos/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Monócitos/metabolismo , Psoríase/etiologia , Psoríase/genética , Pele/efeitos dos fármacos , Pele/metabolismo , Células Th17/metabolismo
3.
Int J Dermatol ; 58(1): 54-59, 2019 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-30168849

RESUMO

BACKGROUND: Tumor necrosis factor inhibitors decrease the risk of cardiovascular events in moderate to severe psoriasis, but the association between their effects on endothelial function and those on skin lesions has not been well studied. We investigated the association between infliximab effects on endothelial function during the loading phase and those on skin lesions in patients with psoriasis. METHODS: We evaluated endothelial function with reactive hyperemia-peripheral arterial tonometry index (RHI) in 15 patients with psoriasis before the first and third infusions of infliximab. Patients were stratified into two groups; those who maintained Psoriasis Area and Severity Index (PASI) 75 response for more than 6 months (defined as responders) and the others (defined as nonresponders). RESULTS: Six weeks after the initiation of infliximab (before the third infusion), PASI scores were significantly improved compared with baseline, while RHI values were not altered in the whole patient group. However, when the responders and the nonresponders were analyzed separately, RHI values tended to be decreased before the third infusion compared with baseline in the nonresponders, while being unchanged in the responders. Importantly, the difference in ∆RHI reached a statistical significance between the two groups, and the cutoff value (mean - 2 standard deviation of RHI values in the responders) identified the nonresponders with 67% of sensitivity and 100% of specificity. CONCLUSIONS: The decrease in RHI values before the third infusion may serve as a predictor for the long-term unfavorable effect of infliximab on psoriatic skin lesions.


Assuntos
Fármacos Dermatológicos/administração & dosagem , Endotélio Vascular/efeitos dos fármacos , Infliximab/administração & dosagem , Psoríase/tratamento farmacológico , Adulto , Idoso , Endotélio Vascular/fisiopatologia , Feminino , Humanos , Hiperemia/induzido quimicamente , Masculino , Manometria , Pessoa de Meia-Idade , Psoríase/patologia , Estudos Retrospectivos , Índice de Gravidade de Doença , Resultado do Tratamento , Fator de Necrose Tumoral alfa/antagonistas & inibidores , Vasodilatação
4.
J Dermatol ; 45(12): 1440-1443, 2018 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-30289574

RESUMO

Serum amyloid A (SAA) is an acute phase protein, which activates immune cells and induces cytokines and chemokine. SAA levels in blood have been reported to be elevated in case of inflammation, infections, neoplasia and tissue injury. In this study, we examined SAA levels in the blood of patients with atopic dermatitis (AD) and cutaneous T-cell lymphoma (CTCL). SAA levels in sera of AD patients, those of CTCL patients and those of healthy controls were not significantly different. When AD or CTCL patients were classified by disease severity, there was still no difference in SAA levels. In AD patients, however, SAA levels positively correlated with the number of eosinophils in peripheral blood and serum soluble interleukin-2 receptor (sIL-2R) levels. There were significant correlations between SAA levels in blood and the number of white blood cells in peripheral blood and serum sIL-2R levels in CTCL patients. AD patients without topical steroid treatment and CTCL patients without narrowband ultraviolet B therapy showed increased levels of SAA, which suggested that SAA levels may easily fluctuate with treatment. These results imply a possible contribution of SAA in development of AD and CTCL.


Assuntos
Dermatite Atópica/sangue , Linfoma Cutâneo de Células T/sangue , Proteína Amiloide A Sérica/análise , Adulto , Dermatite Atópica/diagnóstico , Dermatite Atópica/tratamento farmacológico , Eosinófilos , Feminino , Glucocorticoides/uso terapêutico , Voluntários Saudáveis , Humanos , Contagem de Leucócitos , Linfoma Cutâneo de Células T/diagnóstico , Linfoma Cutâneo de Células T/terapia , Masculino , Pessoa de Meia-Idade , Receptores de Interleucina-2/sangue , Índice de Gravidade de Doença , Resultado do Tratamento , Terapia Ultravioleta
6.
Arch Dermatol Res ; 308(9): 655-660, 2016 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-27591995

RESUMO

Syndecan-4 (SDC-4) is a cell surface proteoglycan, which participates in signaling during cell adhesion, migration, proliferation, endocytosis, and mechanotransduction, and is expressed on various cells, including endothelial cells, epithelial cells, T cells, and eosinophils. Emerging evidences have suggested that SDC-4 might contribute to Th2-driven allergic immune responses. Here, we examined the role of SDC-4 in patients with atopic dermatitis (AD). Serum SDC-4 levels in AD patients were significantly higher than in healthy individuals, and they increased according to the disease severity. Importantly, they positively correlated with Eczema Area and Severity Index and itch visual analogue scale scores. Furthermore, serum SDC-4 levels decreased after treatment. We also analyzed SDC-4 expression in AD lesional skin. SDC-4 mRNA levels in AD skin were significantly higher than those of normal skin. Immunohistochemical staining revealed that SDC-4 was highly expressed in the epidermis and endothelial cells in AD lesional skin. Taken together, our study has demonstrated that SDC-4 expression was increased in sera and skin of AD patients, suggesting that SDC-4 may contribute to the development of AD.


Assuntos
Dermatite Atópica/metabolismo , Epiderme/metabolismo , Prurido/metabolismo , Sindecana-4/metabolismo , Adulto , Dermatite Atópica/sangue , Dermatite Atópica/tratamento farmacológico , Células Endoteliais/metabolismo , Células Epidérmicas , Epiderme/patologia , Feminino , Voluntários Saudáveis , Humanos , Masculino , Pessoa de Meia-Idade , RNA Mensageiro/metabolismo , Índice de Gravidade de Doença , Sindecana-4/sangue , Adulto Jovem
9.
J Dermatol ; 42(7): 723-6, 2015 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-25899120

RESUMO

Galectin-9 is a member of the galectin family that has a wide spectrum of biological functions. Among them, galectin-9 has been known mainly as a potent chemoattractant for eosinophils. In addition, galectin-9 alters the T-cell balance by negatively regulating T-helper (Th)1 and Th17 cells, resulting in Th2 polarization. Atopic dermatitis (AD) is a skin allergic disease characterized by peripheral eosinophilia, mast cell activation and predominance of Th2 cells. To investigate possible roles of galectin-9 in AD, we measured serum galectin-9 levels in AD patients and investigated galectin-9 expression in lesional skin by immunohistochemistry. Serum galectin-9 levels in patients with AD were significantly higher than those in healthy controls and correlated with the Eczema Area and Severity Index. Serum galectin-9 levels were decreased after treatment, accompanied by improvement of skin lesions. Immunohistochemical study revealed that galectin-9 was expressed on epidermal keratinocytes and mast cells in lesional skin of AD. Our results suggest that elevated galectin-9 expression is associated with progression of AD and that galectin-9 could be a therapeutic target in AD.


Assuntos
Dermatite Atópica/sangue , Galectinas/sangue , Adulto , Estudos de Casos e Controles , Dermatite Atópica/metabolismo , Feminino , Galectinas/análise , Humanos , Queratinócitos/química , Masculino , Mastócitos/química , Índice de Gravidade de Doença
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