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 se veral diseases, an imbalance between helper T lymphocytes Th1 and Th2 and their cytokines has been suggested as a contributing factor. In th is study, although IFN-gamma from splenic T cells of D1-DMBA-3 mammary tumor-bearing mice was greatly diminished, other cytokine levels rema ined unchanged, indicating no clear shift between the Th1, Th2, or Th3 phenotypes. The IFN-gamma levels can be restored in vitro by addition of rlL-12 to cultured splenocytes from tumor bearers, Furthermore, IL -12 production is greatly down-regulated in macrophages from tumor-bea ring mice as detected by ELISA, and this correlates with diminished ex pression of IL-12 p40 chain RNA. The mammary tumor used in our studies produces several factors, including granulocyte macrophage-CSF, PGE(2 ), and phosphatidyl serine, that can affect the immune system. Additio n of these tumor-derived factors in vitro to macrophages from normal m ice resulted in decreased levels of IL-12 protein in cultures treated with PGE, or phosphatidyl serine, These results indicate that the down -regulation of T cell-produced IFN-gamma in this tumor model is the re sult of decreased IL-12 production caused by tumor-derived factors and not a shift from the Th1 to the Th2 phenotype.