Wolf Peter, Nghiem Dat X, Walterscheid Jeffrey P, Byrne Scott, Matsumura Yumi, Matsumura Yasuhiro, Bucana Cora, Ananthaswamy Honnavara N, Ullrich Stephen E
Research Unit for Photodermatology, Department of Dermatology, Medical University Graz, Auenbrugger Platz 8, A-8036 Graz, Austria.
Am J Pathol. 2006 Sep;169(3):795-805. doi: 10.2353/ajpath.2006.060079.
Psoralen plus UVA (PUVA) is used as a very effective treatment modality for various diseases, including psoriasis and cutaneous T-cell lymphoma. PUVA-induced immune suppression and/or apoptosis are thought to be responsible for the therapeutic action. However, the molecular mechanisms by which PUVA acts are not well understood. We have previously identified platelet-activating factor (PAF), a potent phospholipid mediator, as a crucial substance triggering ultraviolet B radiation-induced immune suppression. In this study, we used PAF receptor knockout mice, a selective PAF receptor antagonist, a COX-2 inhibitor (presumably blocking downstream effects of PAF), and PAF-like molecules to test the role of PAF receptor binding in PUVA treatment. We found that activation of the PAF pathway is crucial for PUVA-induced immune suppression (as measured by suppression of delayed type hypersensitivity to Candida albicans) and that it plays a role in skin inflammation and apoptosis. Downstream of PAF, interleukin-10 was involved in PUVA-induced immune suppression but not inflammation. Better understanding of PUVA's mechanisms may offer the opportunity to dissect the therapeutic from the detrimental (ie, carcinogenic) effects and/or to develop new drugs (eg, using the PAF pathway) that act like PUVA but have fewer side effects.
补骨脂素加紫外线A（PUVA）被用作治疗多种疾病的非常有效的治疗方式，包括银屑病和皮肤T细胞淋巴瘤。PUVA诱导的免疫抑制和/或细胞凋亡被认为是其治疗作用的原因。然而，PUVA起作用的分子机制尚未完全了解。我们之前已确定血小板活化因子（PAF），一种强效磷脂介质，是触发紫外线B辐射诱导的免疫抑制的关键物质。在本研究中，我们使用PAF受体敲除小鼠、一种选择性PAF受体拮抗剂、一种COX-2抑制剂（可能阻断PAF的下游效应）以及PAF样分子来测试PAF受体结合在PUVA治疗中的作用。我们发现PAF途径的激活对于PUVA诱导的免疫抑制（通过对白色念珠菌迟发型超敏反应的抑制来衡量）至关重要，并且它在皮肤炎症和细胞凋亡中起作用。在PAF的下游，白细胞介素-10参与了PUVA诱导的免疫抑制，但不参与炎症。对PUVA机制的更好理解可能提供机会区分其治疗作用与有害（即致癌）作用，和/或开发像PUVA一样起作用但副作用更少的新药（例如，使用PAF途径）。
