The role of IL-6 in jet fuel irritant 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。接触性皮炎分为两种主要表现，即涉及T细胞的免疫起源（过敏性）或免疫记忆不起作用的非免疫起源（刺激性）。虽然刺激物可能会对皮肤造成明显的损伤，但两种类型的皮炎都会产生非常相似的炎症反应。与皮肤中的刺激物相比，接触致敏剂引起不同的细胞因子/趋化因子谱，但尚不清楚特定细胞因子是否与刺激物类型或强度相关。此外，已知炎性细胞因子与皮肤愈合密切相关，并且特定刺激物对特定细胞因子的调节可能加剧皮肤损伤，从而导致刺激性增加。如果特定的细胞因子可以与刺激性，这可能是显着的预测价值时，判断潜在的刺激性的化学品，或个人的反应，刺激性暴露。有趣的是，JP-8喷气燃料，这是非腐蚀性的，但会导致严重的刺激性皮炎，减少暴露的皮肤中的炎症细胞因子IL-6的表达。由于IL-6与皮肤愈合密切相关，因此提出了皮肤IL-6水平的化学诱导调节有助于皮炎严重性的假设。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引起的损伤之间是否有直接联系。为了研究该IL-6缺陷型和野生型C57小鼠将暴露于刺激物JP 8喷气燃料，以及充分表征的刺激物SLS、BKC和丙酮作为对照。将在暴露1、3、5和7天后收集皮肤样品，并将评估IL-6、IL-6 R、CEBP和SOCS 3 mRNA和蛋白质。将通过皮肤病、组织病理学和免疫组织学的可视化来确定明显损伤的评估。第二个具体目标是研究用外源性或内源性IL-6治疗的可能保护作用。用外源性IL-6治疗将涉及在C57或IL-6 KO小鼠的皮肤中直接皮内注射rmIL-6。将通过使用过表达表皮衍生的细胞因子（Tg（I16）1 Efu）的转基因小鼠模型来研究内源性IL-6的增加。这两种模型都将暴露于所述刺激物。将如上所述评估皮肤病，以及IL-6 R、CEBP和SOCS 3的基因表达，其是IL-6受体活化的方便标志物。 如果这个假设是正确的，IL-6可以被证明是一个有用的标志物，在确定刺激潜力的化学品，以及提供合理的IL-6为基础的治疗，可能会发现在预防或治疗职业性皮炎。 公共卫生相关性：皮肤疾病在工作场所非常常见，在与工人赔偿相关的职业伤害报告中，接触性皮炎排名第二。白细胞介素6是皮肤中产生的一种细胞因子，与愈合密切相关，某些刺激性化学物质，如JP 8喷气燃料，可以减少皮肤中这种因子的量。确定白细胞介素6如何参与皮肤保护免受化学刺激物的影响将有助于预测化学物质的刺激潜力，可能有助于识别易受刺激性皮炎影响的个体，并最终导致基于这种细胞因子的皮炎治疗方法的发展。

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.