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

在抗cd3和IL-12存在的情况下，IL-18被发现是一个促进Thl细胞产生IFN-y的因子。像IL-lp一样，IL-18是作为前体蛋白合成的，需要与caspase-1切割才能变得活跃。随着IL-18在IL-12存在下的生物学作用被研究，IL-18被标记为IFN-Y诱导因子。然而，我们证明了IL-18通过引起CD4* T细胞产生IL-4和表达CD40L而导致正常小鼠产生高水平的IgE。特应性皮炎（AD）是由嗜碱性细胞和肥大细胞的产物引起的瘙痒性皮肤病。由于IL-18直接刺激这些细胞产生IL-4、IL-13和组胺，我们研究了IL-18是否可以在不遇到过敏原或IgE诱导的情况下诱导特应性反应。为此，我们建立了在其角质形成细胞中分别过表达IL-18或caspase-1基因的KCASPlTg或KIL-18Tg。两种转基因小鼠在SPF条件下均产生大量的IL-18、IgE和组胺，并自发发生肥大细胞积累的慢性皮炎。KCASPlTg中stat6基因的缺失完全消除了IgE的产生，但没有消除它们的皮肤变化，这表明IL-18而不是IgE诱导了这些病理变化。接下来，我们建立了缺乏IL-18的KCASPlTg，发现这种缺失几乎完全消除了皮肤的改变。另一方面，KJL-18Tg比KCASPlTg需要更长的时间来显示这些特应性表型。此外，KCASPlTg中IL-1基因的缺失延迟了这种发病。因此，特应性炎症可能由IL-18的过度释放引发，并由IL-1加速。我们的数据可能允许我们提出将特应性分为过敏原/ ige依赖性特应性（获得型过敏）和il -18依赖性但ige非依赖性特应性（先天型过敏）。此外，我们的数据表明，以Caspase-l/IL-18为靶标分子的治疗方法将为我们建立过敏性疾病的治疗提供新的见解。少

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