REGULATION OF INTERLEUKIN 4 GENERATION

SCOR建议的一个主要总体目标是了解如何 炎性细胞浸润哮喘的肺气道。 在 白细胞介素4（IL-4）似乎是其中一个。 调节免疫细胞募集的关键因素 循环以及随后的免疫细胞分化， activation. IL-4作用于T细胞和B细胞， 分化，并可与其他细胞因子协同作用 （特别是IL-3）引起过敏性炎症的完全表达。 IL-4也是诱导细胞粘附的关键决定因素 - 内皮细胞表面上的分子（特别是VCAM-1），和 这种效应可能介导携带α 4 β 1的免疫细胞的募集， 细胞，如T细胞、嗜酸性粒细胞和巨噬细胞。这些IL-4- 驱动事件似乎是哮喘的关键特征，因为免疫- 细胞IL-4和内皮细胞VCAM-1的增加， 哮喘受试者和抗原诱导的气道炎症， 在缺乏IL-4基因或用抗- VCAM-1抗体。 因此，我们推断IL-4产生的控制是 对于调节气道炎症的发展至关重要， 过敏性哮喘 尽管有几种气道细胞类型 我们把工作重点放在抗原上 特异性T细胞在T细胞行为的小鼠模型中， 分泌IL-4的抗原特异性T细胞的主要亚群是 称为辅助性T细胞（Th）2型。Th 2型T细胞具有 增强肺免疫的过敏性的潜力 因为IL-4的一个作用是诱导进一步的Th 2 发展作为过敏循环的放大器， Th 2细胞也是炎症的治疗靶点， 潜在的意义。因此，本项目旨在 确定IL-4产生的分子控制， 随之而来的IL-4作用。 我们之前的研究发现 介导DNA/蛋白质相互作用的IL-4基因启动子 对基因激活至关重要此外，我们还证明了 IL-4和IL-12在T辅助细胞发育中的作用 使用T细胞行为的转基因小鼠模型生产。 我们 利用我们对IL-4生物学广泛定义， 小鼠Th 2型T细胞来定义：（i）新的- 已鉴定的转录因子（命名为Stat 6）在控制 IL-4基因激活;以及（ii）IL-4基因与IL-4基因的关键相互作用 4-依赖于IL-12的活性。然后我们将扩展 这些发现与从非哮喘患者中获得的T细胞的研究结果一致。 和哮喘受试者来确定IL-4的分子异常 产生和行动，可能是负责的发展 气道炎症。

A major overall aim of this SCOR proposal is to understand how inflammatory cells infiltrate the pulmonary airway in asthma. In that context, interleukin-4 (IL-4) appears to be one of the critical factors regulating immune cell recruitment from the circulation as well as subsequent immune cell differentiation and activation. IL-4 acts on T cells and B cells to direct differentiation and can act in concert with other cytokines (notably IL-3) to cause full expression of allergic inflammation. IL-4 is also a key determinant for inducing cell adhesion molecules (notably VCAM-I) on the endothelial cell surface, and this effect may mediate recruitment of alpha4beta1-bearing immune cells, such as T cells, eosinophils, and macrophages. These IL-4- driven events appear to be key features of asthma because immune- cell IL-4 and endothelial-cell VCAM-l are increased in tissue from asthmatic subjects and antigen-induced airway inflammation is blocked in animals lacking the IL-4 gene or treated with anti- VCAM-I antibodies. We therefore reasoned that the control of IL-4 production is critical for regulating the development of airway inflammation in allergic asthma. Although several airway cell types are capable of producing IL-4, we have focused our work on the antigen- specific T cell. In murine models of T cell behavior, the principal subset of antigen-specific T cells that secrete IL-4 is termed T helper (Th) type 2. The Th2-type T cells have the potential to reinforce the allergic character of pulmonary immune response, because one action of IL-4 is to induce further Th2 development. As an amplifier of this cycle of allergic inflammation, the Th2 cell also represents a therapeutic target of potential significance. Accordingly, this project aims at determining the molecular controls for IL-4 generation and consequent IL-4 action. Our previous studies identified elements of the IL-4 gene promoter that mediate DNA/protein interactions critical for gene activation. Further, we have demonstrated the roles of IL-4 and IL-12 on T helper cell development and IL-4 production using transgenic mouse models of T cell behavior. We take advantage of our extensive definition of IL-4 biology in murine Th2-type T cells to define: (i) the role of a newly- identified transcription factor (designated Stat6) in controlling IL-4 gene activation; and (ii) the critical interaction of the IL- 4-dependent activity with the action of IL-12. We will then extend these findings to studies of T cells obtained from nonasthmatic and asthmatic subjects to pinpoint molecular abnormalities in IL-4 generation and action that may be responsible for the development of airway inflammation.