Rambukkana A, Pistoor F H, Bos J D, Kapsenberg M L, Das P K
Department of Dermatology, Academic Medical Center, University of Amsterdam, The Netherlands.
Lab Invest. 1996 Feb;74(2):422-36.
Epidermal Langerhans cells (LC) and cytokines play a critical role in the initiation phase of contact hypersensitivity reactions in the skin. Most of the studies of these aspects have been performed in animal models and relatively little is known about the human system. Short-term human skin organ cultures, in which LC preserved their characteristics and distribution within the epidermis, were used to examine the time course effects of contact allergens on human LC in situ and whether these effects are mediated by cytokines. Epicutaneous application of nontoxic concentrations of contact allergens 2,4-dinitrofluorobenzene, 2,4-dinitrochlorobenzene, and nickel sulphate, but not the irritants sodium dodecylsuphaye and croton oil or the tolerogen 2,4-dichloronitrobenzene, significantly reduced the total number of LC in the epidermis: remaining LC were localized along the epidermal-dermal junction, suggesting a migration of LC within and out of the epidermis. LC that are migrated to the epidermal-dermal junction showed a decreased expression of CD1a+ and MHC-II and an upregulation of ICAM-I. While these effects were observed after 24 hours, the expression of IL-1 beta protein was induced exclusively by LC as early as 4 hours after skin challenge with contact allergens alone. After 24 hours, contact allergens not only increased the expression of IL-1 beta but also induced the expression of IL-1 alpha, TNF-alpha, GM-CSF, and IL-6 proteins mainly by suprabasal keratinocytes. In an attempt to study the possible relation between allergen-induced epidermal cytokines and the migration and phenotypic changes of LC, skin explants were incubated with corresponding human recombinant (hr) cytokines. After 12 hours, hr IL-1 beta, but not other hr cytokines (IL-1 alpha, TNF-alpha, GM-CSF, and IL-6), induced the migration within and out of the epidermis and decreased the expression of CD1a+ and MHC-II on remaining epidermal LC similar to that caused by contact allergens. Pre-incubation of skin explants with neutralizing IL-1 beta antibodies, but not antibodies to IL-1 alpha, TNF-alpha, or GM-CSF, significantly prevented the allergen-induced migration of LC. This study showed that contact allergens preferentially induced the migration of LC within and out of the epidermis and modulated the expression of cell surface molecules on migrated LC as well as induced the early expression of LC-derived IL-1 beta. We also provide evidence that IL-1 beta is critically involved in contact allergen-induced changes on human epidermal LC and suggest that IL-1 beta plays a role in the initiation of contact hypersensitivity in human skin in vivo.
表皮朗格汉斯细胞（LC）和细胞因子在皮肤接触性超敏反应的起始阶段起着关键作用。关于这些方面的大多数研究都是在动物模型中进行的，而对人体系统的了解相对较少。短期人体皮肤器官培养物中，LC在表皮内保持其特征和分布，被用于研究接触性变应原对人体原位LC的时间进程影响，以及这些影响是否由细胞因子介导。经皮应用无毒浓度的接触性变应原2,4-二硝基氟苯、2,4-二硝基氯苯和硫酸镍，但不包括刺激性物质十二烷基硫酸钠和巴豆油或耐受原2,4-二氯硝基苯，可显著减少表皮内LC的总数：剩余的LC位于表皮-真皮交界处，提示LC在表皮内外迁移。迁移至表皮-真皮交界处的LC显示CD1a+和MHC-II表达降低，ICAM-I表达上调。虽然这些效应在24小时后观察到，但早在单独用接触性变应原刺激皮肤4小时后，LC就可单独诱导IL-1β蛋白的表达。24小时后，接触性变应原不仅增加IL-1β的表达，还主要通过基底上层角质形成细胞诱导IL-1α、TNF-α、GM-CSF和IL-6蛋白的表达。为了研究变应原诱导的表皮细胞因子与LC迁移和表型变化之间的可能关系，将皮肤外植体与相应的人重组（hr）细胞因子一起孵育。12小时后，hr IL-1β，但不是其他hr细胞因子（IL-1α、TNF-α、GM-CSF和IL-6），诱导了表皮内外的迁移，并降低了剩余表皮LC上CD1a+和MHC-II的表达，类似于接触性变应原所引起的情况。用中和性IL-1β抗体而非IL-1α、TNF-α或GM-CSF抗体对皮肤外植体进行预孵育可显著阻止变应原诱导的LC迁移。本研究表明，接触性变应原优先诱导LC在表皮内外迁移，调节迁移后LC上细胞表面分子的表达，并诱导LC衍生的IL-1β的早期表达。我们还提供证据表明，IL-1β在接触性变应原诱导的人体表皮LC变化中起关键作用，并提示IL-1β在人体皮肤体内接触性超敏反应的起始中起作用。
