The Role of IL-6 Receptor in Irritant Dermatitis

描述（由申请人提供）：在报告的与工人赔偿相关的职业伤害中，接触性皮炎排名第二。化学刺激性接触性皮炎（ICD）的特点是由细胞因子调节的急性炎症反应。然而，目前尚不清楚是否特定的细胞因子与刺激类型或强度有关。在判断某种化学物质的潜在刺激性或个体对刺激物暴露的反应时，这些知识可能具有重要的预测价值。促炎细胞因子白细胞介素6 （IL-6）与皮肤愈合和屏障维护密切相关。初步数据表明，IL-6缺乏的小鼠比过表达IL-6的小鼠表现出更严重的ICD。因此，我们假设皮肤IL-6功能的调节与皮炎的严重程度有关。提出了三个具体目标。第一个具体目的是研究IL-6的保护作用是否可以通过改变屏障和/或炎症基因表达来表现出来。为了检验这两种可能性，我们将评估几种常见刺激物诱导的ICD期间WT、IL-6KO和Tg （il -6）小鼠皮肤中的差异基因表达。来自小鼠的ICD病变将利用聚焦于炎症和结构基因的PCR阵列进行检查。蛋白表达将通过免疫组织学、多重ELISA和/或Western blot来证实。第二个具体目标将研究[通过评价可溶性蛋白给药IL-6的保护机制]。将蛋白溶液皮内注射到WT或IL-6KO小鼠皮肤中，通过目的1或rmIL-6指示的外源蛋白进行评估。（或者，如果无法获得蛋白质，该基因将通过病毒载体传递到皮肤上）。治疗后，小鼠暴露于

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.