ANTITUMORAL PROTERTIES OF AGED MONOCYTES

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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.