RESUMO
Psoriasis is characterized by hyperproliferation of keratinocytes and by infiltration of activated Th1 and Th17 cells in the (epi)dermis. By expression microarray, we previously found the GATA3 transcription factor significantly downregulated in lesional psoriatic skin. Since GATA3 serves as a key switch in both epidermal and T helper cell differentiation, we investigated its function in psoriasis. Because psoriatic skin inflammation shares many characteristics of epidermal regeneration during wound healing, we also studied GATA3 expression under such conditions.Psoriatic lesional skin showed decreased GATA3 mRNA and protein expression compared to non-lesional skin. GATA3 expression was also markedly decreased in inflamed skin of mice with a psoriasiform dermatitis induced with imiquimod. Tape-stripping of non-lesional skin of patients with psoriasis, a standardized psoriasis-triggering and skin regeneration-inducing technique, reduced the expression of GATA3. In wounded skin of mice, low GATA3 mRNA and protein expression was detected. Taken together, GATA3 expression is downregulated under regenerative and inflammatory hyperproliferative skin conditions. GATA3 expression could be re-induced by successful narrow-band UVB treatment of both human psoriasis and imiquimod-induced psoriasiform dermatitis in mice. The prototypic Th2 cytokine IL-4 was the only cytokine capable of inducing GATA3 in skin explants from healthy donors. Based on these findings we argue that GATA3 serves as a key regulator in psoriatic inflammation, keratinocyte hyperproliferation and skin barrier dysfunction.
Assuntos
Epiderme/metabolismo , Fator de Transcrição GATA3/genética , Interleucina-4/farmacologia , Psoríase/genética , Regeneração/efeitos dos fármacos , Regeneração/efeitos da radiação , Raios Ultravioleta , Adulto , Idoso , Animais , Ciclo Celular/efeitos dos fármacos , Ciclo Celular/genética , Ciclo Celular/efeitos da radiação , Diferenciação Celular/efeitos dos fármacos , Diferenciação Celular/genética , Diferenciação Celular/efeitos da radiação , Núcleo Celular/efeitos dos fármacos , Núcleo Celular/metabolismo , Núcleo Celular/efeitos da radiação , Proliferação de Células/efeitos dos fármacos , Proliferação de Células/efeitos da radiação , Dermatite/complicações , Dermatite/genética , Dermatite/patologia , Epiderme/efeitos dos fármacos , Epiderme/efeitos da radiação , Feminino , Fator de Transcrição GATA3/metabolismo , Perfilação da Expressão Gênica , Humanos , Queratinócitos/efeitos dos fármacos , Queratinócitos/metabolismo , Queratinócitos/patologia , Queratinócitos/efeitos da radiação , Masculino , Camundongos , Pessoa de Meia-Idade , Fototerapia , Transporte Proteico/efeitos dos fármacos , Transporte Proteico/efeitos da radiação , Psoríase/complicações , Psoríase/patologia , Regulação para Cima/efeitos dos fármacos , Regulação para Cima/efeitos da radiação , Adulto JovemRESUMO
Narrow-band ultraviolet-B (NB-UVB) phototherapy is an effective treatment for psoriasis. The molecular mechanisms underlying its efficacy are incompletely understood. To identify NB-UVB-induced molecular pathways that may account for its anti-inflammatory efficacy, gene expression profiling was performed using epidermal RNA from lesional and nonlesional skin from patients with psoriasis undergoing NB-UVB therapy. Downregulation of Th17 signaling pathway was observed during NB-UVB therapy in psoriatic epidermis. Strong inhibition of the Th17 pathway by UVB was confirmed in an ex vivo organ culture system by demonstrating reduced signal transducer and activator of transcription 3 (STAT3) phosphorylation and ß-defensin-2 production. These results were further substantiated by demonstrating that NB-UVB inhibited the Th17-dependent psoriasis-like dermatitis in mice. Other pathways affected by NB-UVB therapy include the IFN signaling pathway, epidermal differentiation, and other well-known therapeutic targets in psoriasis, such as the glucocorticoid, vitamin D, peroxisome proliferator-activated receptor, and IL-4 signaling pathways. In conclusion, clinical improvement of psoriasis by NB-UVB is linked to suppression of Th17 and type I and type II IFN signaling pathways, which are critical in the pathogenesis of the disease. Our results show that clinically effective NB-UVB therapy is based on suppression of a broad range of important molecular pathways in psoriatic skin.
Assuntos
Interferons/antagonistas & inibidores , Psoríase/radioterapia , Transdução de Sinais/fisiologia , Células Th17/fisiologia , Terapia Ultravioleta , Adulto , Idoso , Anticorpos Monoclonais/farmacologia , Anticorpos Monoclonais Humanizados , Diferenciação Celular , Epiderme/metabolismo , Epiderme/patologia , Feminino , Perfilação da Expressão Gênica , Humanos , Interferons/fisiologia , Masculino , Pessoa de Meia-Idade , Psoríase/metabolismo , Psoríase/patologia , UstekinumabRESUMO
BACKGROUND AND OBJECTIVES: Pulsed dye laser (PDL) therapy is effective in clearing psoriasis plaques, but the mechanism of action is only partially understood. Local narrow-band ultraviolet B (NB-UVB), which has a better-defined mode of action, is an effective standard treatment for psoriasis. Our aim was to evaluate the cellular and molecular effects of PDL and to compare them with those of local NB-UVB in order to gain further insight into their mechanisms of action in psoriasis. STUDY DESIGN/PATIENTS AND METHODS: Nineteen patients with stable plaque-type psoriasis were treated either with PDL or NB-UVB. Lesional punch biopsies were obtained from all patients before treatment. Additional biopsies were obtained at 3 and 24 hours after PDL treatment in five of these patients. In 14 patients additional biopsies were taken after 7 and 13 weeks of treatment. Samples were histopathologically examined for the level of dermal T cell infiltrate, and the expression of epidermal beta-defensin 2, immune cell-derived tumor necrosis factor (TNF)-alpha, endothelial E-selectin, vascular endothelial growth factor receptor (VEGFR) 2 and 3, and the expression of interleukin (IL)-23 before and after treatment. RESULTS: The expression of VEGFR2, VEGFR3, and E-selectin was decreased in clinically high responders within 24 hours after PDL treatment. The expression of IL-23, TNF-alpha mRNA, and E-selectin protein were significantly reduced after two PDL treatments, whereas the expression of all epidermal markers and dermal T cell infiltrates had normalized after four treatments. The expression of epidermal activation markers and E-selectin were significantly reduced after 13 weeks of NB-UVB treatment. CONCLUSIONS: The expression of epidermal activation markers and the dermal T cell infiltrates were decreased after both treatments. The decreased expression of VEGFR2 and VEGFR3 followed by the down-regulation of TNF-alpha and IL-23p19 may be contributory factors in the efficacy of PDL in stable plaque-type psoriasis.
Assuntos
Biomarcadores/análise , Lasers de Corante/uso terapêutico , Terapia com Luz de Baixa Intensidade/métodos , Psoríase/patologia , Psoríase/radioterapia , Terapia Ultravioleta/métodos , Adulto , Idoso , Biópsia por Agulha , Biologia Celular , Regulação para Baixo , Selectina E/análise , Selectina E/metabolismo , Feminino , Seguimentos , Humanos , Imuno-Histoquímica , Subunidade p19 da Interleucina-23/análise , Subunidade p19 da Interleucina-23/metabolismo , Masculino , Pessoa de Meia-Idade , Biologia Molecular , Probabilidade , Estudos Prospectivos , Índice de Gravidade de Doença , Estatísticas não Paramétricas , Resultado do Tratamento , Fator de Necrose Tumoral alfa/análise , Fator de Necrose Tumoral alfa/metabolismo , Receptor 1 de Fatores de Crescimento do Endotélio Vascular/análise , Receptor 1 de Fatores de Crescimento do Endotélio Vascular/metabolismo , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/análise , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/metabolismo , Adulto JovemRESUMO
In Catharanthus roseus cell suspensions, the expression of several terpenoid indole alkaloid biosynthetic genes, including two genes encoding strictosidine synthase (STR) and tryptophan decarboxylase (TDC), is coordinately induced by fungal elicitors such as yeast extract. To identify molecular mechanisms regulating the expression of these genes, a yeast one-hybrid screening was performed with an elicitor-responsive part of the TDC promoter. This screening identified three members of the Cys(2)/His(2)-type (transcription factor IIIA-type) zinc finger protein family from C. roseus, ZCT1, ZCT2, and ZCT3. These proteins bind in a sequence-specific manner to the TDC and STR promoters in vitro and repress the activity of these promoters in trans-activation assays. In addition, the ZCT proteins can repress the activating activity of APETALA2/ethylene response-factor domain transcription factors, the ORCAs, on the STR promoter. The expression of the ZCT genes is rapidly induced by yeast extract and methyljasmonate. These results suggest that the ZCT proteins act as repressors in the regulation of elicitor-induced secondary metabolism in C. roseus.