Regulatory mechanisms of neuro-endocine-immune system in the skin

近年来，在日本，患过敏性疾病，特别是特应性皮炎的患者人数不断增加。皮肤屏障功能障碍、向Th 2型免疫应答的转变和血清IgE升高以及对精神和/或身体应激的异常反应被认为是重要的病因和加重因素。众所周知，引起发炎皮肤瘙痒的介质是组胺、前列腺素和速激肽。其中，P物质（SP）在介导外周瘙痒感觉中起着重要作用。我们最近发现SP可以从表皮角质形成细胞或成纤维细胞释放。为了阐明应激反应在Th 2型过敏性炎症中的作用，我们在知情同意的情况下，观察了SP、组胺对IL-4诱导的Th 2型趋化因子，特别是对来源于异位性皮炎皮损的成纤维细胞产生eotaxin的影响，我们观察到SP和组胺在IL-4刺激下协同增加eotaxin的产生和mRNA表达。用RT-PCR和FAGS分析证实，IL-4和SP及/或组胺刺激AD成纤维细胞IL-4受体的表达较IL-4单独刺激时明显增加，SP或组胺刺激AD成纤维细胞IL-4受体的表达明显增加，并持续到第9代。这种异常现象是AD固有的还是获得性的，在本项目中还没有阐明。皮肤驻留细胞通过向Th 2免疫应答的转变在AD中发挥重要作用。IL-4 R、NK 1-R、H1/H2 R基因多态性与Th 2类趋化因子产生的关系是今后研究的重点。

The number of patients suffering allergic diseases, especially atopic dermatitis has been increasing in recent Japan. Dysfunction of skin barrier, shift to Th2 immune response with elevated serum IgE and abnormal response to mental and/or physical stress are thought to be important etiological and exacerbating factors. It was well known that mediators causing itch in inflamed skin is histamine, prostaglandin and tachykinins. Among these, substance P (SP) plays central role to mediate peripheral itch sensation. We have recently found that SP can be released from epidermal keratinocytes or fibroblasts. To clarify stress response on Th2 allergic inflammations, we conducted the effect of SP, histamine on IL4-induced Th2 chemokines, especially eotaxin production by fibroblasts derived from skin lesions of atopic dermatitis under informed consent.We observed that SP and histamine increased synergistically eotaxin production and mRNA expression when stimulated with IL-4. We also proved that the expression of IL-4 receptor in fibroblasts stimulated with IL-4 and SP and /or histamine was increased rather than stimulated with IL-4 alone by RT-PCR and FAGS analysis.This elevated IL4-R expression by SP or histamine was significantly higher and persisted to passage 9 in AD-derived fibroblasts than in normal controls. Whether this aberrant phenomenon was intrinsic or acquired in AD is not clarified in this project. The skin residents cells provide some important roles through the shift to Th2 immune response in AD. Polymorphisms of IL-4R, NK1-R, or H1/H2R genes and their relationship to accerelated Th2 ehemokine production should be studied in the future work for the order made medicine in the future.