CYTOKINE AND ADHESION MOLECULE EXPRESSION IN KAPOSI'S

我们假设由于感染和免疫失调 某些HIV感染患者经历的卡波西肉瘤(KS)细胞 它们的前体暴露在高水平的细胞因子和 感染性病原体的成分，如双链RNA和 脂多糖。我们假设这些药物激活了核因子-kappa- B类转录因子，这种激活有助于 细胞黏附分子在KS细胞上的诱导表达 其前体，从而增强特定类型的粘附性 白细胞。这些药物还可以诱导KS细胞表达IL-6， 提示KS细胞表达的IL-6可能参与了 激活贴壁的白细胞。我们假设这些 白细胞提供因子，包括艾滋病毒的Tat蛋白和 更多的IL-6和肿瘤素M，是血管内皮细胞的中介物 KS的发展。尽管培养中的KS细胞保持着一种 与其他可被认为是候选细胞类型的细胞不同 前体，无论是CAM的表达还是IL-6的表达都不是结构性的 在KS细胞中，表明宿主因素是导致高 在KS皮损中的表达水平。因为核因子-kappa-B 一致的位点存在于CAMS、IL-6和 HIV，共同激活核因子-kappa-B的分子事件可能是 对于导致发展的许多变化和 KS的进展，因此可以作为临床的靶点 干预。我们已经确定了几种干扰机制 核因子-kappa-B通过这些试剂驱动的基因表达。这些实验是 旨在加深我们对CAM和IL-6调节的了解 在KS中的表达及其诱导的功能后果 不同的特工。此外，我们还将探讨 靶向核因子-γ-B样蛋白作为共同转录因子 参与这些基因的表达，可能是一种治疗方法 KS的治疗策略。

We hypothesize that because of infections and immune dysregulation experienced by certain HIV-infected patients, Kaposi's sarcoma (KS) cells and their precursors are exposed to high levels of cytokines and to components of the infectious agents, such as double stranded RNA and lipopolysaccharide. We hypothesize that these agents activate NF-kappa- B-like transcription factors, and that this activation contributes to the induced expression of cellular adhesion molecules (CAMs) on KS cells and their precursors, thereby enhancing adhesion of specific types of leukocytes. These same agents also induce IL-6 expression by KS cells, suggesting that IL-6 expressed by the KS cells might contribute to activation of the adherent leukocytes. We hypothesize that these leukocytes provide factors, including the Tat protein of HIV and additional IL-6 and Oncostatin M, agents that are mediators in the development of KS. Although KS cells in culture maintain a phenotype that is distinct from other cell types that could be considered candidate precursors, neither CAM expression nor IL-6 expression is constitutive in KS cells, suggesting that host factors are responsible for the high levels of expression that occur in KS lesions. Because NF-kappa-B consensus sites exists in the regulatory regions of the CAMs, IL-6 and HIV, the shared molecule event of activation of NF-kappa-B could be necessary for many of the changes that lead to the development and progression of KS, and as such could serve as a target of clinical intervention. We have identified several mechanisms to interfere with NF-kappa-B-driven gene expression by these agents. These experiments are designed to enhance our understanding of the regulation of CAM and IL-6 expression in KS and the functional consequences of their induction by different agents. In addition, we will explore the consequences of targeting NF-gamma-B-like proteins as a shared transcription factor involved in the expression of these genes as a possible therapeutic strategy for the treatment of KS.