RESUMEN
Cutaneous eruption is a common drug-adverse reaction, characterised by keratinocytes inflammation and apoptosis. Shuanghuanglian injeciton (SHLI) is a typical Chinese medicine injection, which is used to treat influenza. It has been reported that SHLI has the potential to induce cutaneous adverse eruptions. However, the mechanisms remain unclear. Since desmoglein 1 (DSG1) shows a crucial role in maintaining skin barrier function and cell susceptibility, we assume that DSG1 plays a critical role in the cutaneous eruptions induced by SHLI. In our study, retinoic acid (RA) was selected to downregulate the DSG1 expression, and lipopolysaccharide (LPS) was first used to identify the susceptibility of the DSG1-deficiency Hacat cells. Then, SHLI was administrated to normal or DSG1-deficient Hacat cells and mice. The inflammatory factors and apoptosis rate were evaluated by RT-PCR and flow cytometry. The skin pathological morphology was observed by hematoxylin and eosin (HE) staining. Our results show that treated only with SHLI could not cause IL-4 and TNF-α mRNA increases in normal Hacat cells. However, in the DSG1-deficient Hacat cells or mice, SHLI induced an extreme increase of IL-4 and TNF-α mRNA levels, as well as in the apoptosis rate. The skin tissue showed a local inflammatory cell infiltration when treated with SHIL in the DSG1-deficient mice. Thus, we concluded that DSG1 deficiency was a potential causation of SHLI induced eruptions. These results indicated that keratinocytes with DSG1 deficiency were likely to induce the cutaneous eruptions when stimulated with other medicines.
Asunto(s)
Apoptosis/efectos de los fármacos , Desmogleína 1/deficiencia , Erupciones por Medicamentos , Medicamentos Herbarios Chinos/efectos adversos , Queratinocitos/metabolismo , Animales , Apoptosis/genética , Línea Celular , Citocinas/genética , Citocinas/metabolismo , Erupciones por Medicamentos/genética , Erupciones por Medicamentos/metabolismo , Erupciones por Medicamentos/patología , Medicamentos Herbarios Chinos/farmacología , Femenino , Queratinocitos/patología , Lipopolisacáridos/toxicidad , Ratones , Ratones Endogámicos ICR , Tretinoina/farmacologíaAsunto(s)
Dermatitis/genética , Desmogleína 1/genética , Hipersensibilidad/genética , Mutación/genética , Síndrome Debilitante/genética , Adulto , Edad de Inicio , Niño , Desmogleína 1/deficiencia , Exoma , Genes Recesivos , Estudio de Asociación del Genoma Completo , Humanos , Queratodermia Palmoplantar/genética , Noruega , Linaje , SíndromeRESUMEN
The desmosomal cadherin desmoglein-1 (DSG1) is an essential intercellular adhesion molecule that is altered in various human cutaneous disorders; however, its regulation and function in allergic disease remains unexplored. Herein, we demonstrate a specific reduction in DSG1 in esophageal biopsies from patients with eosinophilic esophagitis (EoE), an emerging allergic disorder characterized by chronic inflammation within the esophageal mucosa. Further, we show that DSG1 gene silencing weakens esophageal epithelial integrity, and induces cell separation and impaired barrier function (IBF) despite high levels of desmoglein-3. Moreover, DSG1 deficiency induces transcriptional changes that partially overlap with the transcriptome of inflamed esophageal mucosa; notably, periostin (POSTN), a multipotent pro-inflammatory extracellular matrix molecule, is the top induced overlapping gene. We further demonstrate that IBF is a pathological feature in EoE, which can be partially induced through the downregulation of DSG1 by interleukin-13 (IL-13). Taken together, these data identify a functional role for DSG1 and its dysregulation by IL-13 in the pathophysiology of EoE and suggest that the loss of DSG1 may potentiate allergic inflammation through the induction of pro-inflammatory mediators such as POSTN.