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.
Handel-Fernandez
M E
ME
Department of Microbiology and Immunology, University of Miami School of Medicine, FL 33101, USA.
Cheng
X
X
Herbert
L M
LM
Lopez
D M
DM
D000818:Animals; D001483:Base Sequence / Q000235:genetics; D002454:Cell Differentiation / Q000276:immunology; D015536:Down-Regulation / Q000276:immunology*; D005260:Female; D007371:Interferon-gamma / Q000096:biosynthesis* / Q000187:drug effects*; D018664:Interleukin-12 / Q000096:biosynthesis* / Q000494:pharmacology*; D008264:Macrophages / Q000378:metabolism; D008297:Male; D008325:Mammary Neoplasms, Experimental / Q000276:immunology* / Q000378:metabolism*; D051379:Mice; D008807:Mice, Inbred BALB C; D011994:Recombinant Proteins / Q000494:pharmacology; D013601:T-Lymphocytes / Q000187:drug effects / Q000378:metabolism; D018417:Th1 Cells / Q000276:immunology*; D018418:Th2 Cells / Q000276:immunology*; D014407:Tumor Cells, Cultured
D011994:Recombinant Proteins; D018664:Interleukin-12; D007371:Interferon-gamma