Macrophages from D1-DMBA-3 mammary tumor bearing mice have profound alterations in various functions, i.e. diminished antigen presentation, decreased cytolytic activity and depressed synthesis of IL-12. In contrast, these cells display a significant enhancement in the levels of TNF-alpha, which may be involved in the cachexia observed in animals bearing large mammary tumors. The molecular mechanisms involved in the upregulation of TNF-alpha in macrophages from tumor bearers were investigated. 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-life. An analysis of the binding of transcription factors relevant to the TNF-alpha gene regulatory region by electrophoretic mobility shift assays (EMSA) revealed no differences in the binding of any NF-kB complex component between macrophages from normal and tumor bearing mice. Likewise, there were no changes in the binding patterns of SP-1 and 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 production of cytokines in pathological conditions, could be the result of alterations of the production and/or binding of transcription factors.
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