Topical application of imatinib mesylate suppresses vitamin D3 analog-induced dermatitis in Balb/c mice.
Topical application of imatinib mesylate suppresses vitamin D3 analog-induced dermatitis in Balb/c mice.
复制标题
局部应用甲磺酸伊马替尼可抑制 Balb/c 小鼠维生素 D3 类似物诱导的皮炎。
作者：
Seshimo H;Egusa C;Maeda T;Numata T;Okubo Y;Harada K;Ito T.
特应性皮炎（AD）是一种由Th 2细胞介导的过敏性疾病。在AD中，外部刺激的角质形成细胞释放炎性细胞因子，如IL-33和TSLP。炎症细胞浸润皮肤组织并增加血管通透性。因此，我们假设，伊马替尼甲磺酸盐（IMT），抑制血管通透性，可能是一个候选的治疗药物AD。每天向Balb/c小鼠的双耳施用维生素D3类似物（MC 903）以产生应用IMT的鼠AD模型。皮肤病变进行了评估，组织病理学和免疫染色。通过使用真实的实时聚合酶链反应（PCR）和免疫染色评估皮肤中的细胞因子表达，并使用伊文思蓝进行研究，以确定IMT是否抑制组胺引起的血管通透性。用真实的荧光定量PCR和酶联免疫吸附试验（ELISA）检测肿瘤坏死因子-α（TNF-α）/白细胞介素-4（IL-4）诱导的内膜间质细胞（IMT）中TSLP表达的抑制作用。通过蛋白质印迹分析信号转导的激活。局部应用IMT可显著降低耳厚度、伊文思蓝渗漏和抓痕发作。在MC 903诱导的小鼠AD模型中，IMT抑制浸润细胞（CD 4 + T细胞、嗜酸性粒细胞和嗜碱性粒细胞）的数量以及IL-13、IL-33和TSLP的表达，并通过下调MKC中ERK磷酸化来抑制TNF-α/IL-4诱导的TSLP表达。IMT减少了MC 903诱导的小鼠AD模型中的皮肤症状，表明它可能具有作为AD新治疗方法的潜力。
Atopic dermatitis (AD) is an allergic disease mediated by Th2 cells. In AD, externally stimulated keratinocytes release inflammatory cytokines, such as IL‐33 and TSLP. Inflammatory cells infiltrate skin tissue and increase vascular permeability. Therefore, we hypothesized that imatinib mesylate (IMT), which suppresses vascular permeability, may be a candidate therapeutic agent for AD. A vitamin D3 analog (MC903) was administered daily to both ears of Balb/c mice to create a murine AD model to which IMT was applied. The skin lesions were evaluated histopathologically and by immunostaining. Cytokine expression in the skin was assessed by using real‐time polymerase chain reaction (PCR) and immunostaining and was investigated using Evans Blue to determine whether IMT suppressed vascular permeability due to histamine. The suppressive effect of TNF‐α/IL‐4‐induced TSLP expression in primary mouse keratinocytes (MKCs) treated with IMT was then investigated.Tslpgene and protein expression in the lesion was measured using real‐time PCR and ELISA. The activation of signal transduction was analysed by western blotting. Topical application of IMT significantly reduced ear thickness, Evans blue leakage, and scratch onset. IMT suppressed the number of infiltrating cells (CD4+ T cells, eosinophils, and basophils), and the expression of IL‐13, IL‐33, and TSLP in a MC903‐induced, murine AD model and inhibited TNF‐α/IL‐4‐induced TSLP expression via downregulation of ERK phosphorylation in MKCs. IMT reduced the skin symptoms in a MC903‐induced, murine AD model, suggesting that it may have potential as a new treatment for AD.