VCAM 1 EXPRESSION IN ENDOTHELIAL CELLS

过敏性疾病如哮喘的特征是导致 主要是嗜酸性粒细胞和T细胞而不是嗜中性粒细胞的募集。 这种选择性招募发生的机制是研究的重点。 这个提议。 这些机制的阐明可能提供新的靶点 用于哮喘和其他过敏性疾病的治疗干预。 白细胞被靶向炎症部位的内皮细胞， 内皮细胞粘附受体。 这些受体之一，血管细胞 粘附分子-1（VCAM-1）在过敏性血管内皮细胞上表达， 炎症和相互作用的α 4整合素的表面上的 白细胞 α 4整联蛋白存在于所有白细胞上， 中性粒细胞 体内数据证实，VCAM-1和 α 4整联蛋白至少部分负责 在过敏性炎症中观察到白细胞浸润。 我们有 先前证明VCAM-1的表达是由 TNF-α和IL-4的组合，并且已经在体内显示， 细胞因子组合导致VCAM-1在细胞表面的选择性表达， 内皮细胞和α 4-整合素阳性白细胞浸润。 升高 TNF存在于许多炎症性疾病中。 然而，IL-4是 特别是在过敏性疾病中增加， VCAM-1表达。 我们以前已经证明，TNF增加， VCAM-1基因通过两个相邻的kappaB位点转录。 不像 其他kappaB位点，这些位点介导内皮特异性反应， 的tnf IL-4与以下因素协同作用：  协同增加VCAM-1 通过增加VCAM-1 mRNA的半衰期来表达。 IL-4导致两个 VCAM-1表达模式的重要变化：它允许 TNF浓度通常不会引起EC表达增加 粘附分子激活VCAM-1的表达，它基本上 检测变应性炎症部位VCAM-1的表达。 IL-4 VCAM-1 mRNA的介导稳定通过一种独特的机制发生 不涉及IL-4活化的经典JAK/STAT途径， 已经在T细胞中得到了很好的研究。 因此，很可能是组合 TNF和IL-4导致嗜酸性粒细胞和T细胞浸润 特别是过敏性疾病。 我们建议进行研究， 这种“过敏性细胞因子”组合如何调节 VCAM-1表达。

Allergic conditions such as asthma characteristically result in the recruitment of predominantly eosinophils and T cells but not neutrophils. The mechanisms by which this selective recruitment occurs is the focus of this proposal. The elucidation of these mechanisms may provide new targets for therapeutic intervention in asthma and other allergic diseases. Leukocytes are targeted to the endothelium at sites of inflammation by endothelial cell adhesion receptors. One of these receptors, vascular cell adhesion molecule-1 (VCAM-1), is expressed on the endothelium in allergic inflammation and interacts with alpha 4 integrins on the surface of the leukocytes. Alpha4 integrins are found on all leukocytes except neutrophils. In vivo data confirms that the interaction between VCAM-1 and alpha4 integrins is at least in part responsible for the pattern of leukocyte infiltration observed in allergic inflammation. We have previously demonstrated that VCAM-1 expression is regulated by the combination of TNF-alpha and IL-4, and it has been shown in vivo that this cytokine combination causes selective expression of VCAM-1 on the endothelium and an alpha4-integrin-positive leukocyte infiltrate. Elevated TNF is found in many inflammatory conditions. However, IL-4 is specifically increased in allergic diseases where it selectively induces VCAM-1 expression. We have previously demonstrated that TNF increases transcription of the VCAM-1 gene through two adjacent kappaB sites. Unlike other kappaB sites, these sites mediate an endothelial-specific response to TNF. IL-4 acts in concert with  synergistically increasing VCAM-1 expression by increasing the half-life of VCAM-1mRNA. IL-4 causes two important changes in the pattern of VCAM-1 expression:it allows concentrations of TNF that do not normally cause increased expression of EC adhesion molecules to activate VCAM-1 expression, and it substantially prolongs the expression of VCAM-1 at sites of allergic inflammation. IL-4 mediated stabilization of VCAM-1 mRNA occurs through a unique mechanism that does not involve the classic JAK/STAT pathway of IL-4 activation which has been well studied in T cells. Thus it is likely that the combination of TNF and IL-4 result in the infiltration of eosinophils and T cells specifically in allergic diseases. We propose studies to examine the molecular mechanisms of how this "allergic cytokine" combination regulates VCAM-1 expression.