TUMOR CELL MEMBRANE MOLECULE INDUCTION OF MONOCYTE TNF

单核巨噬细胞是宿主重要的防御系统 对抗肿瘤细胞细菌和其他病原体 大量的 有证据表明，单核细胞抗肿瘤的一种重要介质 免疫反应是肿瘤坏死因子α（TNF-α）。 其他研究 表示局部（即在肿瘤细胞微环境中） 单核细胞产生TNF-α，而不是全身水平， 对宿主防御很重要，对宿主毒性较小。 TNF-alpha 代表了几种细胞因子中的一种，这些细胞因子可能在细胞内共同起作用。 免疫应答和调节其他细胞因子的产生， 肿瘤和炎症。 肿瘤细胞与单核细胞的相互作用 在细胞膜水平，以及信号转导通路的触发 导致肿瘤坏死因子-α基因表达，是这项资助的主题 提议 在过去的几年里，我们的实验室已经纯化和表征了一种新的 48 kd分化因子（DF），称为P48，最初从肿瘤中分离 细胞条件培养基（CM）。 后来发现这种DF诱导外周 血液单核细胞分泌TNF-α和IL-1，并作为一个整体存在 膜形式（称为mP48）在一些肿瘤细胞系上。 肿瘤细胞 已知可诱导单核细胞TNF-α产生，在该提案中，我们 目前的证据表明，mP48是一种肿瘤细胞膜分子， 介导肿瘤细胞-单核细胞相互作用，导致TNF-α分泌。 因此，我们建议（1）鉴定和表征单核细胞 肿瘤细胞上受mP48刺激的表面受体;（2）确定 mP48诱导单核细胞TNF-α分泌的机制;和（3） 确定P48多肽与膜脂的生化连接， 为了开始确定mP48和P48的关系， 厘米 详细了解肿瘤细胞-单核细胞相互作用， TNF-α的产生可能会促进我们对肿瘤的理解 并可能导致非全身性细胞因子的改进方法 癌症的免疫治疗。

Mononuclear phagocytes are known to be an important system of host defense against tumor cells, bacteria, and other pathogens. A large body of evidence indicates that one important mediator of monocyte anti-tumor immune response is Tumor Necrosis Factor Alpha (TNF-alpha). Other studies indicate that local (i.e. in the microenvironment of the tumor cell) production of TNF-alpha by monocytes, rather than systemic levels, are more important to host defense and less toxic to the host. TNF-alpha represents one of several cytokines which are likely to act together in the immune response and modulate production of other cytokines at the site of tumors and inflammation. The interaction between tumor cells and monocytes at the membrane level, and the triggering of signal transduction pathways leading to TNF-alpha gene expression, are the subjects of this grant proposal. Over the last several years, our lab has purified and characterized a new 48 kd differentiation factor (DF) termed P48, initially isolated from tumor cell conditioned medium (CM). This DF was later found to induce peripheral blood monocytes to secrete TNF-alpha and IL-1 and to exist as an integral membrane form (termed mP48) on some tumor cell lines. Tumor cells are known to induce monocyte TNF-alpha production, and in this proposal we present evidence that mP48 is one tumor cell membrane molecule which mediates tumor cell-monocyte interaction leading to TNF-alpha secretion. We, therefore, propose to (1) identify and characterize the monocyte surface receptor which is stimulated by mP48 on tumor cells; (2) determine the-mechanism by which mP48 induces monocyte TNF-alpha secretion; and (3) determine the biochemical linkage of P48 polypeptide to membrane lipid in order to begin to determine the relationship between mP48 and P48 found in CM. A detailed understanding of tumor cell-monocyte interaction leading to TNF-alpha production will likely advance our understanding of tumor immunology and may lead to improved methods of non-systemic cytokine immunotherapy of cancer.