The Role of IL-6 Receptor in Irritant Dermatitis

IL-6 受体在刺激性皮炎中的作用

• 批准号: 8733191
• 负责人: RANDLE Michael GALLUCCI
• 金额: $ 49.41万
• 依托单位: UNIVERSITY OF OKLAHOMA HLTH SCIENCES CTR
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-09-01 至 2017-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8733191
• 关键词: Role; IL; Receptor; Irritant; Dermatitis

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.

描述（由申请人提供）：在报告的与工人赔偿有关的职业伤害中，接触性皮炎在所有职业伤害中排名第二。化学刺激性接触性皮炎（ICD）的特征是由细胞因子调节的急性炎症反应。然而，目前尚不清楚特定的细胞因子是否与刺激物的类型或强度相关。在判断化学品的刺激性潜力或个人对刺激性暴露的反应时，这种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持密切相关。初步数据表明，IL-6缺陷小鼠比WT或IL-6过表达小鼠表现出更严重的ICD。因此，提出皮肤IL-6功能的调节有助于皮炎的严重性的假设。 提出了三个具体目标。第一个具体目标将研究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。为了检查这两种可能性，将评估由几种常见刺激物诱导的ICD期间WT、IL-6 KO和Tg（IL 6）小鼠皮肤中的差异基因表达。将利用聚焦于炎症和结构基因的PCR阵列来检查来自小鼠的ICD病变。将通过免疫组织学、多重ELISA和/或Western印迹确认蛋白表达。 第二个具体目标是研究[通过评价可溶性蛋白给药的IL-6保护机制]。[目的1所示的外源蛋白或rmIL-6将通过]将蛋白溶液皮内注射到WT或IL-6 KO小鼠的皮肤中进行评价。[或者，如果不能获得蛋白质，则基因将通过病毒载体递送到皮肤]。一旦处理，小鼠暴露于 化学刺激物和炎症的程度将通过可视化和组织病理学来确定。 第三个具体目标是研究与IL- 6相关的基因的已知多态性（SNP）是否通过调节该细胞因子的表达或其受体的功能而导致人类ICD易感性。将对斑贴试验患者的样本进行55个IL-6相关基因SNP筛查。将通过QPCR确定多态性，并进行统计分析以显示与病理学的相关性。[To为了进一步研究SNPs的机制，将产生表达与ICD严重程度强烈相关的人类基因SNPs的转基因小鼠，以直接模拟人类病理学。将按照具体目标1所述评估ICD。] 如果这一假设是正确的，IL-6将被证明是一个有用的标志物，在确定刺激潜力的化学品，以及是否某些人群可能更容易发展ICD。这项研究也可能为基于IL-6的治疗提供合理性，这些治疗可能用于预防或治疗职业性皮炎。