Down-regulation of IL-12, not a shift from a T helper-1 to a T helper-2 phenotype, is responsible for impaired IFN-gamma production in mammary tumor-bearing mice.

Altered cytokine production has been implicated in the down-regulation of cell-mediated immunity in mice bearing large mammary tumors. In several diseases, an imbalance between helper T lymphocytes Th1 and Th2 and their cytokines has been suggested as a contributing factor. In this study, although IFN-gamma from splenic T cells of D1-DMBA-3 mammary tumor-bearing mice was greatly diminished, other cytokine levels remained unchanged, indicating no clear shift between the Th1, Th2, or Th3 phenotypes. The IFN-gamma levels can be restored in vitro by addition of rIL-12 to cultured splenocytes from tumor bearers. Furthermore, IL-12 production is greatly down-regulated in macrophages from tumor-bearing mice as detected by ELISA, and this correlates with diminished expression of IL-12 p40 chain RNA. The mammary tumor used in our studies produces several factors, including granulocyte macrophage-CSF, PGE2, and phosphatidyl serine, that can affect the immune system. Addition of these tumor-derived factors in vitro to macrophages from normal mice resulted in decreased levels of IL-12 protein in cultures treated with PGE2 or phosphatidyl serine. These results indicate that the down-regulation of T cell-produced IFN-gamma in this tumor model is the result of decreased IL-12 production caused by tumor-derived factors and not a shift from the Th1 to the Th2 phenotype.