TUMOR CELL MEMBRANE MOLECULE INDUCTION OF MONOCYTE TNF

单核巨噬细胞是一种重要的宿主防御系统。 抗肿瘤细胞、细菌和其他病原体。一大堆 证据表明，单核细胞抗肿瘤的一个重要介质 免疫反应是肿瘤坏死因子-α(TNF-α)。其他研究 表明局部(即在肿瘤细胞的微环境中) 单核细胞比全身水平产生的肿瘤坏死因子-α更多。 对宿主防御很重要，对宿主毒性较小。肿瘤坏死因子-α 代表几种细胞因子中的一种，这些细胞因子可能在 免疫反应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 在膜水平上，以及信号转导通路的触发 导致肿瘤坏死因子-α基因的表达，都是这项拨款的主题 求婚。 在过去的几年里，我们的实验室提纯并鉴定了一种新的 48kd的分化因子，命名为P48，最初从肿瘤中分离出来 细胞条件培养液(CM)。这种DF后来被发现能诱发外周血肿 血单核细胞分泌肿瘤坏死因子-α和白介素1并作为一个整体存在 在某些肿瘤细胞系上形成膜(称为MP48)。肿瘤细胞是 已知可以诱导单核细胞产生肿瘤坏死因子-α，在这个建议中，我们 目前有证据表明，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，导致肿瘤坏死因子-α的分泌。 因此，我们建议(1)鉴定和表征单核细胞 MP48刺激肿瘤细胞表面受体；(2)测定 MP48诱导单核细胞分泌肿瘤坏死因子-α的机制； 测定P48多肽与细胞膜脂质的生化连接 开始确定MP48和P48之间的关系 厘米。详细了解肿瘤细胞-单核细胞相互作用导致 肿瘤坏死因子-α的产生可能会促进我们对肿瘤的理解 免疫学，并可能导致非系统性细胞因子的改进方法 癌症的免疫疗法。

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.