REGULATION OF VCAM-1 EXPRESSION BY INTERLEUKIN 4

炎性细胞的渗透似乎是导致许多 哮喘发生在哮喘呼吸道的病理变化。 循环中的炎性细胞与内皮细胞的黏附 将这些细胞募集到肺中的第一步。 血管细胞黏附分子-1(VCAM-1)出现在肺上 哮喘患者和新兵循环中嗜酸性粒细胞和血管内皮细胞的变化 淋巴细胞与α4β1和α4β1的相互作用 这些细胞表面有α4β7整合素。其中一个 细胞因子已被证明在哮喘患者中增加 呼吸道是IL-4。有一些证据表明IL-4是遗传的 与过敏性哮喘有关，并敲除小鼠的IL-4基因 或添加抗IL-4抗体可预防显著的 对肺部过敏原攻击的炎症反应， 这表明这种细胞因子对高效的 过敏性炎症反应。其他细胞因子，如肿瘤 肿瘤坏死因子-α(TNF-α)和IL-1也升高。 哮喘患者。我们发现这些细胞因子和IL-4一起 在选择性和协同诱导中发挥重要作用 血管细胞黏附分子-1在人肺微血管内皮细胞的表达 细胞。肿瘤坏死因子和白介素1导致血管细胞黏附分子-1的转录激活 基因通过启动子中的kappaB位点，而IL-4稳定 由此产生的消息导致了 血管细胞黏附分子-1的表达与血管细胞黏附分子-1在血管内皮细胞上的延长 内皮表面。总而言之，这些结果表明 IL-4在选择性增加VCAM-1中的重要作用 表达导致嗜酸性粒细胞和淋巴细胞的募集 射到肺里。我们发现IL-4使VCAM-1mRNA增加 通过一种新的机制实现稳定，该机制不涉及 传统的JAK/STAT途径为IL-4信号转导途径。 因此，我们建议研究这一新的信号传递方式。 途径和定义分子事件导致 VCAM-1mRNA的稳定化。这将涉及到两个互补的 方法：L)一种由内而外识别IL-4的方法 调节血管细胞黏附分子-L基因表达的反应性胞浆蛋白(S) 稳定性，并利用该蛋白发现细胞质 导致IL-4受体的相互作用；2)“由外而内” 从IL-4受体开始到IL-4的途径 调节VCAM-1mRNA的反应性胞浆靶蛋白 稳定性。为IL-4之间的功能联系提供证据 和VCAM-1的表达及炎性细胞的募集 体内，我们将VCAM-1的表达与浸润性相关 炎症细胞进入小鼠肺对变应原的反应 在野生型和IL-4基因敲除小鼠中挑战。AS 以上所述，血管细胞黏附分子-L、白介素I、肿瘤坏死因子、白介素4的表达 在哮喘患者中被证明是增加的。我们建议延长 这些研究通过将VCAM-1、IL-4和 肿瘤坏死因子在空间和时间上的变化 嗜酸性粒细胞和淋巴细胞对人体呼吸道的影响 对节段性变应原的反应--吸入刺激和停用 糖皮质激素治疗。这些研究将包括过敏和 先天哮喘患者。嗜酸性粒细胞渗入是其特征 这两种情况都有。尽管有证据表明IL-4的作用 和VCAM-1在过敏性哮喘炎症细胞募集中的作用 在内源性哮喘中发挥相应作用的证据仍需 待定。

Infiltration of inflammatory cells appears responsible for many of the pathologic changes that occur in the asthmatic airway. Adhesion of circulating inflammatory cells to the endothelium is the first step in recruitment of these cells to the lung. Vascular cell adhesion molecule-1 (VCAM-1) appears on the lung endothelium in asthmatics and recruits circulating eosinophils and lymphocytes through its interaction with alpha4beta1 and alpha4beta7 integrins on the surface of these cells. One of the cytokines that has been shown to be increased in the asthmatic airway is IL-4. There is some evidence that IL-4 is genetically linked to allergic asthma, and knocking out the IL-4 gene in mice or addition of anti-IL-4 antibody prevents a significant inflammatory response to allergen challenge in the lung, suggesting that this cytokine is critical for an efficient allergic inflammatory response. Other cytokines such as tumor necrosis factor-alpha (TNF) and IL-1 are also increased in asthmatics. We have found that these cytokines along with IL-4 play an important role in selectively and synergistically inducing expression of VCAM-1 on human pulmonary microvascular endothelial cells. TNF and IL-1 cause transcriptional activation of the VCAM-1 gene through kappaB sites in the promoter, whereas IL-4 stabilizes the resulting messages leading to both a synergistic increase in VCAM-1 expression and the prolonged appearance of VCAM-1 on the endothelial surface. Taken together, these results suggest that IL-4 plays an important role in selectively increasing VCAM-1 expression leading to recruitment of eosinophils and lymphocytes to the lung. We have found that IL-4 increases VCAM-1 mRNA stability through a novel mechanism that does not involve the traditional JAK/STAT pathway of IL-4 signal transduction. Therefore, we propose studies to examine this novel signaling pathway and to define molecular events leading to the stabilization of VCAM-1 mRNA. This will involve two complementary approaches: l) an "inside-out" approach to identify an IL-4 responsive cytoplasmic protein(s) that regulates VCAM-l mRNA stability, and to use this protein to discover cytoplasmic interactions leading back to the IL-4 receptor; 2) an "outside-in" approach beginning with the IL-4 receptor and leading to the IL-4 responsive cytoplasmic target protein that regulates VCAM-1 mRNA stability. To provide evidence of the functional link between IL-4 and VCAM-1 expression and recruitment of inflammatory cells in vivo, we will correlate expression of VCAM-1 with the infiltration of inflammatory cells into the mouse lung in response to allergen challenge in both wild-type and IL-4 gene knockout mice. As mentioned above, expression of VCAM-l, IL-I, TNF, and IL-4 have been shown to be increased in asthmatics. We propose to extend these studies by correlating the expression of VCAM-1, IL-4, and TNF both spatially and temporally with the recruitment of eosinophils and lymphocytes to the airway of human subjects in response to segmental allergen-challenge and withdrawal of inhaled glucocorticoid therapy. These studies will include allergic and intrinsic asthmatics. An eosinophil infiltrate is characteristic of both conditions. Although there is evidence of a role for IL-4 and VCAM-1 in inflammatory cell recruitment in allergic asthma, evidence for a corresponding role in intrinsic asthma still needs to be defined.