The Role of IL-6 Receptor in Irritant Dermatitis

描述(申请人提供)：在报告的与工人补偿有关的职业伤害中，接触性皮炎在所有人中排名第二。化学刺激性接触性皮炎(ICD)是一种受细胞因子调节的急性炎症反应。然而，目前还不清楚特定的细胞因子是否与刺激物的类型或强度有关。在判断一种化学物质的刺激性潜力或个体对刺激性暴露的反应时，这些知识可能具有重要的预测价值。促炎细胞因子白介素6(IL-6)与皮肤愈合和屏障维护密切相关。初步数据显示，IL-6缺乏的小鼠表现出比WT或IL-6过度表达的小鼠更严重的ICD。因此，该假说认为皮肤IL-6功能的调节有助于皮炎的严重程度。提出了三个具体目标。第一个特定目标将研究IL-6的保护作用是否可能通过改变屏障和/或炎症基因表达而表现出来。为了检验这两种可能性，我们将评估WT、IL-6KO和TG(IL6)小鼠在几种常见刺激物诱导的ICD期间皮肤中的差异基因表达。将利用专注于炎症和结构基因的聚合酶链式反应阵列检查小鼠的ICD损伤。蛋白表达将通过免疫组织学、多重ELISA法和/或Western印迹来确认。第二个具体目标是[通过评估可溶性蛋白给药来探讨IL-6的保护机制]。[Aim One，或rmIL-6指示的外源蛋白将通过]皮内注射蛋白溶液到WT或IL-6KO小鼠的皮肤中进行评估。[或者，如果不能获得一种蛋白质，基因将通过病毒载体传递到皮肤]。一旦接受治疗，小鼠就会暴露在 化学刺激物和炎症程度将通过可视化和组织病理学来确定。第三个具体目标将调查与IL-6相关的基因的已知多态性(SNPs)是否通过调节这种细胞因子的表达或其受体的功能而导致人类对ICD的易感性。来自斑贴测试患者的样本将被筛选出55个IL-6相关基因SNPs。多态将通过定量聚合酶链式反应确定，并将进行统计分析，以显示与病理的相关性。为了进一步研究SNPs的机制，将产生表达与ICD严重程度密切相关的人类基因SNPs的转基因小鼠，以直接模拟人类的病理。ICD将按照具体目标一中所述进行评估。]如果这一提议的假设是正确的，IL-6将被证明是一种有用的标记物，用于确定一种化学物质的刺激性潜力，以及某些人群是否更容易发生ICD。这项研究也可能为基于IL-6的治疗方法在职业性皮炎的预防或治疗中的应用提供理论依据。

DESCRIPTION (provided by applicant): Of reported occupational injury associated with workman's compensation, contact dermatitis ranks second most prevalent over all. Chemical irritant contact dermatitis (ICD) is characterized by an acute inflammatory response that is modulated by cytokines. However, it is not known if specific cytokines are associated with irritant type or strength. This knowledge may be of significant predictive value when judging the irritancy potential of a chemical, or an individual's response to irritant exposure. The proinflammatory cytokine interleukin 6 (IL-6) is closely associated with skin healing and barrier maintenance. Preliminary data indicate that mice deficient in IL-6 display more severe ICD than WT or IL-6 overexpressing mice. Thus, the hypothesis is proposed that modulation of skin IL-6 function contributes to severity of dermatitis. Three specific aims are proposed. The first specific aim will investigate whether the protective effects of IL-6 could manifest themselves through altered barrier and/or inflammatory gene expression. To examine both possibilities, differential gene expression in skin of WT, IL-6KO and Tg (IL6) mice during ICD induced by several common irritants will be assessed. ICD lesions from mice will be examined utilizing PCR arrays focusing on inflammatory and structural genes. Protein expression will be confirmed via immunohistology, multiplex ELISA and/or Western blot. The second specific aim will investigate [the protective mechanism of IL-6 through evaluation of soluble protein administration]. [Exogenous proteins indicated by aim one, or rmIL-6 will be evaluated by] intradermal injection of the protein solution into skin of WT or IL-6KO mice. [Alternately, if a protein cannot be acquired, the gene will be delivered to skin via a viral vector]. Once treated, mice are exposed to chemical irritants and the extent of inflammation will be determined by visualization and histopathology. The third specific aim will investigate whether known polymorphisms (SNPs) of genes associated with IL- 6 contribute to ICD susceptibility in humans through the modulation of expression of this cytokine, or the function of its receptor. Samples from patch-tested patients will be screened for 55 IL-6 associated gene SNPs. Polymorphisms will be determined by QPCR, and statistical analysis will be performed to show correlations to pathology. [To further investigate the mechanisms of SNPs, transgenic mice that express human gene SNPs that are strongly associated with ICD severity, will be generated to directly model the human pathology. ICD will be assessed as described in specific aim one.] If the hypothesis of this proposal is correct, IL-6 would prove to be a useful marker in determining irritancy potential of a chemical, and whether certain populations may be more prone to developing ICD. This research may also provide the rational for IL-6 based therapies that may find use in the prophylaxis or treatment of occupational dermatitis.