ABSTRACT
Aberrant inflammation, such as that associated with inflammatory bowel disease (IBD), is fueled by the inordinate activity of RelA/NF-κB factors. As such, the canonical NF-κB module mediates controlled nuclear activation of RelA dimers from the latent cytoplasmic complexes. What provokes pathological RelA activity in the colitogenic gut remains unclear. The noncanonical NF-κB pathway typically promotes immune organogenesis involving Nfkb2 gene products. Because NF-κB pathways are intertwined, we asked whether noncanonical signaling aggravated inflammatory RelA activity. Our investigation revealed frequent engagement of the noncanonical pathway in human IBD. In a mouse model of experimental colitis, we established that Nfkb2-mediated regulations escalated the RelA-driven proinflammatory gene response in intestinal epithelial cells, exacerbating the infiltration of inflammatory cells and colon pathologies. Our mechanistic studies clarified that cell-autonomous Nfkb2 signaling supplemented latent NF-κB dimers, leading to a hyperactive canonical RelA response in the inflamed colon. In sum, the regulation of latent NF-κB dimers appears to link noncanonical Nfkb2 signaling to RelA-driven inflammatory pathologies and may provide for therapeutic targets.
Subject(s)
Inflammation/pathology , Intestines/pathology , NF-kappa B p52 Subunit/metabolism , NF-kappa B/metabolism , Protein Multimerization , Signal Transduction , Transcription Factor RelA/metabolism , Animals , Colitis/metabolism , Colitis/pathology , Disease Progression , Epithelial Cells/metabolism , Homeostasis , Humans , Inflammation/metabolism , Inflammatory Bowel Diseases/metabolism , Inflammatory Bowel Diseases/pathology , Lymphotoxin beta Receptor/metabolism , Mice, Inbred C57BL , Models, Biological , NF-kappa B p52 Subunit/deficiency , Stromal Cells/metabolismABSTRACT
Monocytes and macrophages are major components of the tumor microenvironment, but their contributions to human cancer are poorly understood. We used molecular profiling combined with functional assays to investigate the role of these cells in human renal cell carcinoma (RCC). Blood monocytes from RCC patients displayed a tumor-promoting transcriptional profile that supported functions like angiogenesis and invasion. Induction of this protumor phenotype required an interleukin-1 receptor (IL-1R)-dependent mechanism. Indeed, targeting of IL-1-IL-1R axis in a human RCC xenograft model abrogated the protumor phenotype of tumor-associated macrophages (TAMs) and reduced tumor growth in vivo. Supporting this, meta-analysis of gene expression from human RCC tumors showed IL1B expression to correlate with myelomonocytic markers, protumor genes, and tumor staging. Analyzing RCC patient tumors confirmed the protumor phenotype of TAMs. These data provide direct evidence for a tumor-promoting role of monocytes and macrophages in human cancer and indicate IL-1-IL-1R as a possible therapeutic target.
Subject(s)
Carcinoma, Renal Cell/immunology , Interleukin-1beta/immunology , Macrophages/immunology , Monocytes/immunology , Receptors, Interleukin-1/immunology , Animals , Cell Proliferation/genetics , Cytokines/biosynthesis , Cytokines/immunology , Gene Expression Profiling , Humans , Inflammation/immunology , Interleukin 1 Receptor Antagonist Protein/pharmacology , Interleukin-1beta/antagonists & inhibitors , Interleukin-1beta/biosynthesis , Interleukin-1beta/genetics , Mice , Mice, Knockout , Mice, SCID , Myeloid Differentiation Factor 88 , Neoplasm Transplantation , Neovascularization, Pathologic , Receptors, Interleukin-1/antagonists & inhibitors , Receptors, Interleukin-1/genetics , Transcription Factor RelA/genetics , Transplantation, Heterologous , Tumor Cells, CulturedABSTRACT
Repeated exposure to low doses of endotoxin results in progressive hyporesponsiveness to subsequent endotoxin challenge, a phenomenon known as endotoxin tolerance. In spite of its clinical significance in sepsis and characterization of the TLR4 signaling pathway as the principal endotoxin detection mechanism, the molecular determinants that induce tolerance remain obscure. We investigated the role of the TRIF/IFN-beta pathway in TLR4-induced endotoxin tolerance. Lipid A-induced homotolerance was characterized by the down-regulation of MyD88-dependent proinflammatory cytokines TNF-alpha and CCL3, but up-regulation of TRIF-dependent cytokine IFN-beta. This correlated with a molecular phenotype of defective NF-kappaB activation but a functional TRIF-dependent STAT1 signaling. Tolerance-induced suppression of TNF-alpha and CCL3 expression was significantly relieved by TRIF and IFN regulatory factor 3 deficiency, suggesting the involvement of the TRIF pathway in tolerance. Alternatively, selective activation of TRIF by poly(I:C)-induced tolerance to lipid A. Furthermore, pretreatment with rIFN-beta also induced tolerance, whereas addition of IFN-beta-neutralizing Ab during the tolerization partially alleviated tolerance to lipid A but not TLR2-induced endotoxin homo- or heterotolerance. Furthermore, IFNAR1-/- murine embryonal fibroblast and bone-marrow derived macrophages failed to induce tolerance. Together, these observations constitute evidence for a role of the TRIF/IFN-beta pathway in the regulation of lipid A/TLR4-mediated endotoxin homotolerance.
