VCAM 1 EXPRESSION IN ENDOTHELIAL CELLS

过敏性疾病，如哮喘，通常会导致 募集主要是嗜酸性粒细胞和T细胞，而不是中性粒细胞。 发生这种选择性招募的机制是 这项提议。对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。 在炎症部位，白细胞被靶向内皮。 内皮细胞黏附受体。其中一种受体是血管细胞 黏附分子-1(VCAM-1)在变态反应性血管内皮细胞上的表达 炎症并与细胞表面的α4整合素相互作用 白细胞。Alpha4整合素在所有白细胞上都有发现，除了 中性粒细胞。体内数据证实VCAM-1和VCAM-1之间的相互作用 α4整合素至少在一定程度上导致了 变态反应性炎症中可见白细胞浸润。我们有 先前证明VCAM-1的表达受 肿瘤坏死因子-α和白介素4的结合，体内实验表明这一点 细胞因子联合诱导血管细胞黏附分子-1选择性表达 内皮细胞和α4整合素阳性的白细胞浸润。高架 肿瘤坏死因子存在于多种炎症状态。然而，IL-4是 特别是在它选择性诱导的过敏性疾病中增加 VCAM-1的表达。我们之前已经证明，肿瘤坏死因子会增加 VCAM-1基因通过两个相邻的kappaB位点转录。不像 其他kappaB位点，这些位点介导内皮细胞特异性的反应 肿瘤坏死因子。IL-4与协同增加的VCAM-1协同作用 通过增加VCAM-1mRNA的半衰期表达。IL-4引起两种 VCAM-1表达模式的重要变化：它允许 通常不会导致EC表达增加的肿瘤坏死因子浓度 黏附分子激活VCAM-1的表达，它实质上 延长VCAM-1在变态反应性炎症部位的表达。白介素4 血管细胞黏附分子-1通过一种独特的机制实现稳定 这不涉及经典的JAK/STAT途径的IL-4激活 已经在T细胞中得到了很好的研究。因此，很可能是这种组合 肿瘤坏死因子和白介素4导致嗜酸性粒细胞和T细胞的浸润 尤其是在过敏性疾病方面。我们建议进行研究，以研究 这种“过敏性细胞因子”组合调节的分子机制 VCAM-1的表达。

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.