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

IL-18被发现是在抗CD3抗体和IL-12存在的情况下促进Thl细胞产生干扰素-γ的因子。与IL-LP一样，IL-18是作为前体蛋白合成的，需要与caspase-1切割才能激活。由于IL-18在IL-12存在下的生物学作用已被研究，因此IL-18被认为是一种干扰素-γ诱导因子。然而，我们证明，当给正常小鼠使用IL-18时，通过促使CD4*T细胞产生IL-4并表达CD40L，导致高水平的IgE产生。特应性皮炎(AD)是由嗜碱性粒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KCASPlTg或KIL-18Tg，它们分别在角质形成细胞中过表达IL-18或Caspase-1基因。两种类型的转基因小鼠都产生了较大的a…在SPF条件下，IL-18、IgE和组胺的积聚更多，并自发地发生肥大细胞堆积的慢性皮炎。KCASPlTg中STAT6基因的缺失完全抑制了IgE的产生，但没有消除皮肤的变化，提示IL-18而不是IgE导致了这些病理变化。接下来，我们建立了缺乏IL-18的KCASPlTg，并发现这种缺失几乎完全消除了皮肤交替。另一方面，KJL-18Tg显示这些特应性表型的时间比KCASPlTg长得多。此外，KCASPlTg中IL-1基因的缺失延缓了这一发病。因此，特应性炎症可能由IL-18的过度释放引起，并被IL-1加速。我们的数据可能使我们建议将特应性疾病分为过敏原/IgE依赖型特应性(获得性变态反应)和IL-18依赖但IgE非依赖型特应性(先天型变态反应)。此外，我们的数据表明，以Caspase-L/IL-18为靶分子的治疗方法将为过敏性疾病的治疗提供新的视角。较少

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