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Mucosal Immunol ; 10(2): 421-433, 2017 03.
Article in English | MEDLINE | ID: mdl-27301879

ABSTRACT

Enterotoxigenic Bacteroides fragilis (ETBF), a human commensal and candidate pathogen in colorectal cancer (CRC), is a potent initiator of interleukin-17 (IL-17)-dependent colon tumorigenesis in MinApc+/- mice. We examined the role of IL-17 and ETBF on the differentiation of myeloid cells into myeloid-derived suppressor cells (MDSCs) and tumor-associated macrophages, which are known to promote tumorigenesis. The myeloid compartment associated with ETBF-induced colon tumorigenesis in Min mice was defined using flow cytometry and gene expression profiling. Cell-sorted immature myeloid cells were functionally assayed for inhibition of T-cell proliferation and inducible nitric oxide synthase expression to delineate MDSC populations. A comparison of ETBF infection with that of other oncogenic bacteria (Fusobacterium nucleatum or pks+Escherichia coli) revealed a specific, ETBF-associated colonic immune infiltrate. ETBF-triggered colon tumorigenesis is associated with an IL-17-driven myeloid signature characterized by subversion of steady-state myelopoiesis in favor of the generation of protumoral monocytic-MDSCs (MO-MDSCs). Combined action of the B. fragilis enterotoxin BFT and IL-17 on colonic epithelial cells promoted the differentiation of MO-MDSCs, which selectively upregulated Arg1 and Nos2, produced NO, and suppressed T-cell proliferation. Evidence of a pathogenic inflammatory signature in humans colonized with ETBF may allow for the identification of populations at risk for developing colon cancer.


Subject(s)
Bacteroides Infections/immunology , Bacteroides fragilis/immunology , Colon/microbiology , Colorectal Neoplasms/immunology , Epithelial Cells/immunology , Myeloid-Derived Suppressor Cells/immunology , T-Lymphocytes/immunology , Animals , Arginase/genetics , Arginase/metabolism , Bacterial Toxins/immunology , Carcinogenesis , Cell Differentiation , Cell Proliferation , Cells, Cultured , Colon/immunology , Colon/pathology , Colorectal Neoplasms/genetics , Disease Models, Animal , Genes, APC , Humans , Immune Tolerance , Interleukin-17/metabolism , Metalloendopeptidases/immunology , Mice , Mice, Inbred C57BL , Mice, Mutant Strains , Nitric Oxide Synthase Type II/genetics , Nitric Oxide Synthase Type II/metabolism , Transcriptome
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