ALTERED BINDING OF THE NF-GMA TRANSCRIPTION FACTOR IS INVOLVED IN THEUP-REGULATED PRODUCTION OF TNF-ALPHA BY MACROPHAGES OF MAMMARY-TUMOR BEARING MICE

Macrophages from D1-DMBA-3 mammary tumor bearing mice have profound al terations in various functions, i.e, diminished antigen presentation, decreased cytolytic activity and depressed synthesis of IL-12. In cont rast, these cells display a significant enhancement in the levels of T NF-alpha, which may be involved in the cachexia observed in animals be aring large mammary tumors. The molecular mechanisms involved in the u pregulation of TNF-alpha in macrophages from tumor bearers were invest igated. The levels of TNF-alpha RNA were increased in macrophages from tumor bearers, but, this was not due to an increase in the RNA half-l ife. An analysis of the binding of transcription factors relevant to t he TNF-alpha gene regulatory region by electrophoretic mobility shift assays (EMSA) revealed no differences in the binding of any NF-kappa B complex component between macrophages from normal and tumor bearing m ice. Likewise, there were no changes in the binding patterns of SP-1 a nd NF-Y. In contrast, the binding of the transcription factor, NF-GMa, was altered in macrophages from tumor bearers. Our results and those reported in other models of disease suggest that the excessive product ion of cytokines in pathological conditions, could be the result of al terations of the production and/or binding of transcription factors.