Therapeutic approach to allergic disorders by focusing on Caspase-1/IL18.

以 Caspase-1/IL18 为重点的过敏性疾病治疗方法。

基本信息

批准号：
11557039
负责人：
NAKANISHI Kenji
金额：
$ 8.26万
依托单位：
HYOGO COLLEGE OF MEDICINE
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (B)
财政年份：
1999
资助国家：
日本
起止时间：
1999 至 2001
项目状态：
已结题

项目摘要

IL-18 was discovered as a factor that enhances IFN-y production from Thl cells in the presence of anti-CD3 and IL-12.Like IL-lp, IL-18 is synthesized as a precursor protein that requires cleavage with caspase-1 to become active. As biological action of IL-18 had been investigated under the presence of IL-12, IL-18 had been rabelled as an IFN-Y inducing factor. However, we demonstrated that IL-18 causes high-level IgE production when administered to normal mice by causing CD4* T cells to produce IL-4 and to express CD40L.Atopic dermatitis (AD) is pruritic skin disease induced by the products of basophils and mast cells. As IL-18 directly stimulates these cells to produce IL-4, IL-13 and histamine, we investigated whether IL-18 can induce atopic response without being encountered with allergen or IgE induction. For this purpose, we established KCASPlTg or KIL-18Tg which over-express IL-18 or caspase-1 gene in their keratinocytes, respectively.Both types of transgenic mice produce large a … More mounts of IL-18, IgE and histamine and spontaneously develop chronic dermatitis accumulated with mast cells under SPF condition. Deletion of stat6 gene in KCASPlTg completely abrogated IgE production without eliminating their cutaneous changes, suggesting that IL-18 but not IgE induces these pathological changes. We next established KCASPlTg lacking IL-18 and found that this depletion almost completely abrogated cutaneous alternation. On the other hand, KJL-18Tg took much longer time to display these atopic phenotypes than KCASPlTg. Moreover, depletion of IL-1 gene in KCASPlTg delayed this onset. Therefore, atopic inflammation might be initiated by over-release of IL-18 and accelerated by IL-1.Our data may allow us to propose to classify atopy to allergen/ IgE-dependent atopy (acquired type allergy) and IL-18-dependent but IgE-independent atopy (innate type allergy). Furthermore, our data suggest that therapeutic approach focusing on Caspase-l/IL-18 as a target molecule will provide us a new insight into the establishment of the treatment for allergic disorder. Less

在存在抗CD3和IL-122的情况下，发现IL-18是增强THL细胞IFN-Y产生的因素，例如IL-LP，IL-18被合成为需要用caspase-1裂解才能活跃的前体蛋白。由于已经在IL-12的存在下研究了IL-18的生物学作用，因此IL-18被视为IFN-y诱导因子。但是，我们证明，当对正常小鼠给药时，IL-18会导致高级IgE产生，通过导致CD4* T细胞产生IL-4并表达CD40L。特性皮肤炎（AD）是由嗜碱性粒细胞和肥料细胞的产物引起的核皮肤病。由于IL-18直接刺激这些细胞产生IL-4，IL-13和组胺，因此我们研究了IL-18是否可以诱导特应反应而不会遇到过敏原或IgE诱导。为此，我们建立了KCASPLTG或KIL-18TG，分别在其角质形成细胞中过表达IL-18或caspase-1基因。多种类型的转基因小鼠类型产生了更多的IL-18，IL-18，IL-18，IgE和组胺，以及具有MSACTORPER SPERED SPERED PERMATIS IPACERED SPFS INFER MEDENS SPFF的IL-18，IL-18，以及spfs spff spff。 kcaspltg中Stat6基因的删除完全消除了IgE的产生，而没有消除其皮肤变化，这表明IL-18但不影响IgE会影响这些病理变化。接下来，我们建立了缺乏IL-18的KCASPLTG，发现这种部署几乎完全是皮肤的替代方案。另一方面，KJL-18TG比KCASPLTG花了更长的时间来显示这些特应性表型。此外，KCASPLTG中IL-1基因的耗竭延迟了这一发作。因此，特应性炎症可能是通过IL-18的过度释放而引发的，并由IL-1加速。此外，我们的数据表明，专注于caspase-l/il-18作为目标分子的治疗方法将为我们提供新的见解，以实现过敏性疾病治疗的建立。较少的