ANTITUMORAL PROTERTIES OF AGED MONOCYTES

我们的初步数据显示“老化的单核细胞”，即纯化的单核细胞 来自老年人(65岁或以上)的，当在体外比较时 年轻的单核细胞，即从年轻的捐赠者那里提纯的单核细胞(25 年平均)部分或全部丧失对肿瘤的细胞毒性 细胞株，并呈现出急剧减少的生产和分泌 一种非常重要的抗肿瘤细胞因子，IL.因此，看起来老年人 单核细胞表现出缺乏的细胞毒性。这些发现可能与 随着年龄的增长，肿瘤的发病率也在增加。低分子量 GTP结合蛋白(LMW-G蛋白)Rho和Rac已被证明是 控制细胞激活，细胞生长和细胞毒性，细胞运动， 吞噬作用、趋化作用、细胞内小泡超氧化物试剂和 分泌细胞毒性颗粒。因此，LMW-G蛋白Rho和Rac 都是必不可少的，不仅对于由 细胞毒与靶细胞之间的接触，也在间接 细胞毒性。RHO和\或RAC功能或信号中的任何缺陷 信号转导途径将改变和减弱细胞的细胞毒性。我们的 初步数据显示，有可能将LMW-G-蛋白、cAMP、 蛋白激酶C、细胞活化和细胞毒作用及单核细胞抗肿瘤功能。 由于老化的单核细胞对肿瘤细胞的杀伤作用不足 体外和LMW-G蛋白控制细胞毒作用 本提案的目的是确定是否存在功能缺陷 LMW-G蛋白是导致衰老单核细胞缺乏的原因 细胞毒性及其与LMW-G蛋白功能缺陷的关系 表达不同的细胞毒机制。因此，具体目标是 这项建议的内容如下： 1.测定低分子量GTP结合蛋白 (LMW-G蛋白)Rac和Rho分别控制细胞激活和细胞 老化单核细胞的细胞毒性。 2.测定老年单核细胞中蛋白激酶的相互关系 C(PKC)和Rho和Rac，并确定PKC是否可以作为效应器 对Rho和RAC来说。 3.测定老年单核细胞中cAMP与cAMP的关系 (CAMP)和Rho和Rac，并确定cAMP是否可能是一个效应器 对Rho和RAC来说。 4.确定LMW-G蛋白中的缺陷是否可能与 随着衰老的单核细胞的细胞毒性特性的缺陷(铁受体， 补体受体L，吞噬，趋化(f-蛋氨酸-亮氨酸-苯丙氨酸)和 超氧化物分子的生产]。 5.确定LMW-G-蛋白的缺陷是否会导致 白介素6等抗肿瘤单因子的产生与肿瘤 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.