title: IL-11-induced reduction of C/EBP transcription factor binding may contribute to the IL-12 downregulation in tumor-bearing mice.
abstract: Using a mammary tumor model syngeneic to BALB/c mice, we have characterized several tumor-derived factors. We now report that the DA-3 cell line derived from this tumor, as well as the in vivo tumor itself, express IL-11. The expression of IL-11 in the tumor is detectable at the transcriptional and translational levels, as evidenced by RT-PCR and Western blots. Using a murine IL-11 ELISA, we observed no differences in IL-11 production between normal and tumor-bearer's macrophages or T cells, with or without activation. Interestingly, elevated levels of IL-11 were found in the sera of tumor-bearers, when compared to normal animals and even higher levels of IL-11 were detected in the tumor cystic fluid. Macrophages from mice bearing large mammary tumors show an impaired production of IL-12 and NO, whereas T cells from the same animals display a deficient production of IFN-gamma. Pretreatment of normal macrophages with IL-11 resulted in no decrease in NO production, nor an impaired production of IFN-gamma was observed in normal T cells upon pretreatment with IL-11. However, pretreatment of normal macrophages with IL-11 resulted in a decreased production of IL-12, as revealed by ELISA and RT-PCR. Electromobility shift assays showed decreased binding of the transcription factor C/EBP to the IL-12p40 promoter of LPS-activated macrophages from normal animals, upon pretreatment with IL-11. In contrast, no differences were observed in the levels of NFkappaB binding under the same experimental conditions. Our results suggest that tumor-derived IL-11 may play a role in the depressed IL-12 production by macrophages, leading to the impaired immune functions observed during mammary tumorigenesis.
authors.affiliation: Department of Microbiology and Immunology, University of Miami School of Medicine, Miami, FL 33136, USA.
authors.forename: Marta
authors.initials: M
authors.lastname: Torroella-Kouri
authors.forename: James C
authors.initials: JC
authors.lastname: Keith
authors.forename: Milena
authors.initials: M
authors.lastname: Ivanova
authors.forename: Diana M
authors.initials: DM
authors.lastname: Lopez
mesh_terms: D000230:Adenocarcinoma / Q000378:metabolism*; D000818:Animals; D022762:CCAAT-Enhancer-Binding Proteins / Q000378:metabolism*; D004273:DNA, Neoplasm / Q000378:metabolism*; D003864:Depression, Chemical; D024202:Electrophoretic Mobility Shift Assay; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects*; D007371:Interferon-gamma / Q000096:biosynthesis / Q000235:genetics; D017370:Interleukin-11 / Q000096:biosynthesis / Q000097:blood / Q000494:pharmacology*; D018664:Interleukin-12 / Q000096:biosynthesis* / Q000235:genetics; D053762:Interleukin-12 Subunit p40; D008070:Lipopolysaccharides / Q000494:pharmacology; D008213:Lymphocyte Activation / Q000187:drug effects; D008262:Macrophage Activation / Q000187:drug effects; D017737:Macrophages, Peritoneal / Q000187:drug effects / Q000378:metabolism; D008297:Male; D008325:Mammary Neoplasms, Experimental / Q000276:immunology / Q000378:metabolism*; D051379:Mice; D008807:Mice, Inbred BALB C; D016328:NF-kappa B / Q000378:metabolism; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism*; D009368:Neoplasm Transplantation; D009569:Nitric Oxide / Q000096:biosynthesis; D011401:Promoter Regions, Genetic; D011485:Protein Binding / Q000187:drug effects; D014176:Protein Biosynthesis; D021122:Protein Subunits / Q000096:biosynthesis* / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013601:T-Lymphocytes / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D014158:Transcription, Genetic / Q000187:drug effects*; D014407:Tumor Cells, Cultured / Q000378:metabolism
chemical_list: D022762:CCAAT-Enhancer-Binding Proteins; D004273:DNA, Neoplasm; D017370:Interleukin-11; D053762:Interleukin-12 Subunit p40; D008070:Lipopolysaccharides; D016328:NF-kappa B; D009363:Neoplasm Proteins; D021122:Protein Subunits; D018664:Interleukin-12; D009569:Nitric Oxide; D007371:Interferon-gamma