TUMOR CELL MEMBRANE MOLECULE INDUCTION OF MONOCYTE TNF

已知单核吞噬细胞是宿主防御的重要系统 对抗肿瘤细胞、细菌和其他病原体。 庞大的身躯 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 表明局部（即在肿瘤细胞的微环境中） 单核细胞产生的 TNF-α，而不是全身水平，更 对宿主防御很重要，并且对宿主毒性较小。 肿瘤坏死因子-α 代表可能在体内共同作用的几种细胞因子之一 免疫反应并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之间的相互作用 在膜水平上，以及信号转导途径的触发 导致 TNF-α 基因表达，是本次资助的主题 提案。 在过去的几年里，我们的实验室纯化并表征了一种新的 48 kd 分化因子 (DF)，称为 P48，最初从肿瘤中分离出来 细胞条件培养基（CM）。 后来发现这种 DF 会诱导外周 血液单核细胞分泌 TNF-α 和 IL-1 并作为一个整体存在 某些肿瘤细胞系上的膜形式（称为 mP48）。 肿瘤细胞是 已知可诱导单核细胞 TNF-α 产生，在本提案中，我们 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）识别和表征单核细胞 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 之间的关系 厘米。 对肿瘤细胞-单核细胞相互作用的详细了解导致 TNF-α的产生可能会增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方法的改进 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.