The role of IL-6 in jet fuel 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。接触性皮炎分为两种主要表现，免疫性皮炎(过敏性)涉及T细胞，非免疫性皮炎(刺激性)免疫记忆不起作用。虽然刺激物可能会对皮肤造成明显的损害，但这两种皮炎产生的炎症反应非常相似。与皮肤刺激物相比，接触性致敏剂可诱发不同的细胞因子/趋化因子谱，但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有关。此外，已知炎性细胞因子与皮肤愈合密切相关，而特定刺激物对特定细胞因子的调节可能会加剧皮肤损伤，从而增加刺激性。如果特定的细胞因子与刺激性有关，这在判断化学物质的刺激性潜力或个体对刺激性暴露的反应时可能具有显著的预测价值。有趣的是，JP-8喷气燃料无腐蚀性，但会导致严重的刺激性皮炎，减少暴露皮肤中炎性细胞因子IL-6的表达。由于IL-6与皮肤愈合密切相关，因此提出了一种假说，即化学诱导的皮肤IL-6水平的调节有助于皮炎的严重程度。提出了两个具体目标。第一个具体目标将调查这种细胞因子的皮肤表达与化学刺激物造成的损害之间是否存在直接联系。为了研究这种IL-6缺乏的野生型C57小鼠，将暴露于刺激物JP8喷气燃料，以及特征良好的刺激物SLS、BKC和丙酮作为对照。暴露后1天、3天、5天和7天将采集皮肤样本，并将评估IL-6、IL-6R、CEBP和SOCS3的mRNA和蛋白。明确损害的评估将通过皮肤病、组织病理学和免疫组织学的可视化来确定。第二个具体目标将调查外源性或内源性IL-6治疗可能的保护作用。外源性IL-6的治疗将包括将rmIL-6直接皮内注射到C57或IL-6KO小鼠的皮肤。内源性IL-6的增强将通过使用过度表达表皮衍生细胞因子(Tg(IL6)1Efu)的转基因小鼠模型来研究。如上所述，这两种模型都会暴露在刺激物中。皮炎将进行如上所述的评估，IL-6R、CEBP和SOCS3的基因表达也将被评估，这些基因是IL-6受体激活的便捷标记。如果这一提议的假设是正确的，IL-6可能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，并为基于IL-6的疗法在职业性皮炎的预防或治疗中的应用提供依据。 公共卫生相关性：皮肤疾病在工作场所非常常见，报告的与工人补偿有关的职业伤害，接触性皮炎在所有疾病中排名第二。白介素6是一种在皮肤中产生的与愈合密切相关的细胞因子，某些刺激性化学物质，如JP8喷气燃料，可以减少皮肤中这一因子的数量。确定白细胞介素6如何参与保护皮肤免受化学刺激，将有助于预测一种化学物质的刺激性潜力，可能有助于确定哪些人容易患刺激性皮炎，并最终可能导致基于这种细胞因子的皮炎治疗方法的开发。

DESCRIPTION (provided by applicant): Of reported occupational injury associated with workman's compensation, contact dermatitis ranks second most prevalent over all. Contact dermatitis is divided into two main manifestations, that of immunological origin (allergic) where T Cells are involved, or non- immunological origin (irritant) where immune memory does not play a role. While irritants may cause overt damage to the skin, both types of dermatitis produce very similar inflammatory responses. Contact sensitizers elicit different cytokine/chemokine profiles as compared to irritants in skin, yet it is not known if specific cytokines are associated with irritant type or strength. Additionally, inflammatory cytokines are known to be closely involved in skin healing, and modulation of specific cytokines by specific irritants could exacerbate skin damage contributing to increased irritancy. If specific cytokines can be associated with irritancy, this may be of significant predictive value when judging the irritancy potential of a chemical, or the response of an individual to irritant exposure. Interestingly JP-8 jet fuel, which is non-corrosive yet causes severe irritant dermatitis, decreases the expression of the inflammatory cytokine IL-6 in exposed skin. Because IL-6 is closely associated with skin healing, the hypothesis is proposed that chemically induced modulation of skin IL-6 levels contributes to severity of dermatitis. Two specific aims are proposed. The first specific aim will investigate whether there is a direct link between the skin expression of this cytokine and damage caused by a chemical irritant. To investigate this IL-6 deficient and wild type C57 mice will be exposed to the irritants JP8 jet fuel, as well as the well characterized irritants SLS, BKC, and acetone as a control. Skin samples will be collected after 1, 3, 5, and 7 days of exposure, and will be assessed for IL-6, IL- 6R, CEBP and SOCS3 mRNA and protein Assessment of overt damage will be determined by visualization of dermatoses, histopathology, and immunohistology. The second specific aim will investigate possible protective effects of treatment with exogenous or endogenous IL-6. Treatment with exogenous IL-6 will involve the direct intradermal injection of rmIL-6 in skin of C57 or IL-6KO mice. Augmentation of endogenous IL-6 will be investigate through the use of the a transgenic mouse model that overexpresses epidermally derived cytokine (Tg(Il6)1Efu). Both of these models will be exposed to irritants as described. Dermatitis will be assessed as described above, as will gene expression for IL-6R, CEBP and SOCS3 which are convenient markers of IL-6 receptor activation. If the hypothesis of this proposal is correct, IL-6 could prove to be a useful marker in determining irritancy potential of a chemical, as well as provide the rational for IL-6 based therapies that may find use in the prophylaxis or treatment of occupational dermatitis. Public Health Relevance: Disorders of the skin are very common in the work place and of reported occupational injury associated with workman's compensation, contact dermatitis ranks second most prevalent over all. Interleukin 6 is a cytokine produced in skin that is closely associated with healing, and certain irritant chemicals such as JP8 jet fuel, can decrease the amount of this factor in the skin. Determining how interleukin 6 is involved in skin protection from chemical irritants will aid in prediction of a chemical's irritancy potential, may help identify individuals who are susceptible to irritant dermatitis, and could eventually result in the development of therapies for dermatitis based on this cytokine.