ANTITUMORAL PROTERTIES OF AGED MONOCYTES

我们的初步数据表明，“老化的单核细胞”，即纯化的单核细胞， 来自老年个体（65岁或以上），当在体外进行比较时 用“年轻单核细胞”，即从年轻供体纯化的单核细胞（25 年平均）部分或全部丧失其抗肿瘤细胞毒性 细胞系，并提出了一个急剧下降的生产和分泌 一种非常重要的抗肿瘤细胞因子IL 1。由此看来，老年人 单核细胞表现出缺乏细胞毒性。这些发现可能与 随着年龄的增长，肿瘤的发病率也会增加。低分子量 GTP结合蛋白（LMW-G蛋白）Rho和Rac已被证明 控制细胞活化，细胞生长和细胞毒性，细胞运动， 吞噬作用、趋化性、胞内囊泡超氧化物试剂和 细胞毒性颗粒的分泌。因此，LMW-G蛋白Rho和Rac 是必不可少的，不仅是由细胞产生的信号转导， 细胞毒性和靶细胞之间的接触，而且在间接 细胞毒Rho和/或Rac功能或信号的任何缺陷 转导途径将改变和减少细胞的细胞毒性。我们 初步数据表明，LMW-G蛋白，cAMP， PKC、细胞活化和细胞毒性以及单核细胞抗肿瘤功能。 由于衰老的单核细胞对肿瘤细胞的细胞毒性不足， 体外和LMW-G蛋白控制细胞毒性细胞中的细胞毒性， 本提案的目的是确定功能缺陷是否 在LMW-G蛋白中， 细胞毒性，以及LMW-G蛋白功能的这种缺陷与细胞毒性的关系。 不同细胞毒性机制的表达。因此，具体目标 这一建议是： 1. 为了确定低分子量GTP结合蛋白是否 （LMW-G蛋白）Rac和Rho分别控制细胞活化和细胞凋亡。 老化单核细胞的细胞毒性。 2. 确定衰老单核细胞中蛋白激酶与 蛋白激酶C（PKC）和Rho和Rac，并确定PKC是否可能是一个效应器， 为了罗和拉克 3. 确定衰老单核细胞中环磷酸腺苷与 （cAMP）和Rho和Rac，并确定cAMP是否可能是效应子。 为了罗和拉克 4. 为了确定LMW-G蛋白的缺陷是否与 由于老化单核细胞的细胞毒性特性的缺陷（Fe-受体， 补体受体1、吞噬作用、趋化性（f-Met-Leu-Phe）和 超氧化物分子的产生]。 5.为了确定LMW-G-蛋白的缺陷是否会引起LMW-G-蛋白的改变， 抗肿瘤单核因子如白细胞介素6的产生与肿瘤 坏死因子。

Our preliminary data show that "aged monocytes," i.e. monocytes purified from aged individuals (65 years of age or more), when compared in vitro with "young monocytes," i.e. monocytes purified from younger donors (25 years average) lose partially or totally their cytotoxicity against tumor cell lines and present a sharp decrease in the production and secretion of a very important antitumoral cytokine, ILl. Therefore, it appears that aged monocytes present a deficient cytotoxicity. These findings may correlate with the increased incidence of tumors with aging. The Low Molecular Weight GTP-binding proteins (LMW-G-proteins) Rho and Rac have been shown to control cell activation, cell growth and cytotoxicity, cell motility, phagocytosis, chemotaxis, intracellular vesicle superoxide reagents and the secretion of cytotoxic granules. Therefore, the LMW-G-proteins Rho and Rac are essential, not only for the signal transduction generated by the contact between cytotoxic and target cell, but also in the indirect cytotoxicity. Any deficiency in the Rho and\or Rac functions or signal transduction pathways will alter and diminish the cell cytotoxicity. Our preliminary data show that it is possible to link LMW-G-proteins, cAMP, PKC, cell activation and cytotoxicity and monocyte antitumoral functions. Since aged monocytes have a deficient cytotoxicity against tumor cells in vitro and LMW-G-proteins control cell cytotoxicity in cytotoxic cells, the purpose of the present proposal is to determine whether a functional defect in LMW-G-proteins is responsible for the aged monocytes' lack of cytotoxicity and how this defect in LMW-G-protein function relates to the expression of distinct cytotoxic mechanisms. Therefore, the specific aims of this proposal are:. 1. To determine whether the Low Molecular Weight GTP-binding protein (LMW-G-proteins) Rac and Rho respectively control cell activation and cell cytotoxicity in aged monocytes. 2. To determine in aged monocytes the relationship between Protein Kinase C (PKC) and Rho and Rac and to determine whether PKC could be an effector for Rho and Rac. 3. To determine in aged monocytes the relationship between cyclic AMP (cAMP) and Rho and Rac and to determine whether cAMP could be an effector for Rho and Rac. 4. To determine whether a defect in LMW-G-proteins could be correlated with a deficiency in the aged monocytes' cytotoxic properties (Fe-Receptor, Complement Receptor l, phatocytosis, chemotaxis (f-Met-Leu-Phe) and production of superoxide molecules]. 5.To determine whether a defect in LMW-G-proteins induces an alteration in the production of antitumoral monokines such as Interleukin 6 and Tumor Necrosis Factor.