RESUMO
Although in the past, keratinocytes were considered simply as passive targets of immunological attack from infiltrating T lymphocytes, a number of studies have definitively demonstrated that keratinocytes actively participate in the cutaneous immune responses. Upon activation, keratinocytes express a plethora of cytokines, chemokines and accessory molecules, which can transmit both positive and negative signals to cells of innate and adaptive immunity. Dysregulation and abnormal expression of inflammatory mediators or their receptors in keratinocytes are relevant to the pathogenesis of chronic inflammatory skin diseases such as psoriasis, atopic dermatitis and allergic contact dermatitis.
Assuntos
Dermatite/patologia , Queratinócitos/patologia , Animais , Doença Crônica , Dermatite Atópica/patologia , Dermatite de Contato/patologia , Humanos , Queratinócitos/fisiologia , Psoríase/patologiaAssuntos
Proteínas de Transporte/genética , Regulação da Expressão Gênica/imunologia , Interferon gama/farmacologia , Peptídeos e Proteínas de Sinalização Intracelular , Queratinócitos/imunologia , RNA Mensageiro/genética , Quimiocinas/genética , Regulação da Expressão Gênica/efeitos dos fármacos , Humanos , Queratinócitos/efeitos dos fármacos , Proteínas Repressoras/efeitos dos fármacos , Proteínas Repressoras/genética , Pele/efeitos dos fármacos , Pele/imunologia , Proteína 1 Supressora da Sinalização de Citocina , Proteínas Supressoras da Sinalização de CitocinaRESUMO
The epidermis of the skin is a self-renewing, stratified epithelium that functions as the interface between the human body and the outer environment, and acts as a barrier to water loss. Components of intercellular junctions, such as Claudins, are critical to maintain tissue integrity and water retention. p63 is a transcription factor essential for proliferation of stem cells and for stratification in epithelia, mutated in human hereditary syndromes characterized by ectodermal dysplasia. Both p63 and Claudin-1 null mice die within few hours from birth due to dehydration from severe skin abnormalities. These observations suggested the possibility that these two genes might be linked in one regulatory pathway with p63 possibly regulating Claudin-1 expression. Here we show that silencing of DeltaNp63 in primary mouse keratinocytes results in a marked down-regulation of Claudin-1 expression (-80%). DeltaNp63alpha binds in vivo to the Claudin-1 promoter and activates both the endogenous Claudin-1 gene and a reporter vector containing a -1.4 Kb promoter fragment of the Claudin-1 gene. Accordingly, Claudin-1 expression was absent in the skin of E15.5 p63 null mice and natural p63 mutant proteins, specifically those found in Ankyloblepharon-Ectodermal dysplasia-Clefting (AEC) patients, were indeed altered in their capacity to regulate Claudin-1 transcription. This correlates with deficient Claudin-1 expression in the epidermis of an AEC patient carrying the I537T p63 mutation. Notably, AEC patients display skin fragility similar to what observed in the epidermis of Claudin-1 and p63 null mice. These findings reinforce the hypothesis that these two genes might be linked in a common regulatory pathway and that Claudin-1 may is an important p63 target gene involved in the pathogenesis of ectodermal dysplasias.