title: Glioma Stem Cells but Not Bulk Glioma Cells Upregulate IL-6 Secretion in Microglia/Brain Macrophages via Toll-like Receptor 4 Signaling.
abstract: Peripheral macrophages and resident microglia constitute the dominant glioma-infiltrating cells. The tumor induces an immunosuppressive and tumor-supportive phenotype in these glioma-associated microglia/brain macrophages (GAMs). A subpopulation of glioma cells acts as glioma stem cells (GSCs). We explored the interaction between GSCs and GAMs. Using CD133 as a marker of stemness, we enriched for or deprived the mouse glioma cell line GL261 of GSCs by fluorescence-activated cell sorting (FACS). Over the same period of time, 100 CD133(+ )GSCs had the capacity to form a tumor of comparable size to the ones formed by 10,000 CD133(-) GL261 cells. In IL-6(-/-) mice, only tumors formed by CD133(+ )cells were smaller compared with wild type. After stimulation of primary cultured microglia with medium from CD133-enriched GL261 glioma cells, we observed an selective upregulation in microglial IL-6 secretion dependent on Toll-like receptor (TLR) 4. Our results show that GSCs, but not the bulk glioma cells, initiate microglial IL-6 secretion via TLR4 signaling and that IL-6 regulates glioma growth by supporting GSCs. Using human glioma tissue, we could confirm the finding that GAMs are the major source of IL-6 in the tumor context.
authors.affiliation: From the Cellular Neurosciences, Max Delbrück Center for Molecular Medicine (MDC), Berlin, Germany (ODaD, FH, VH, SAW, HK) ; Department of Neurosurgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, People's Republic of China (FH); Department of Neurology (KD, PE), Center for Stroke Research Berlin, Department of Experimental Neurology, Department of Neurology (PE, CH), Department of Neurology and Center for Anatomy, Institute of Cell Biology and Neurobiology (SL), Charité - Universitätsmedizin Berlin, Charitéplatz 1, Berlin, Germany; and Department of Neurosurgery, University of Schleswig-Holstein, Campus Kiel, Kiel, Germany (MS).
authors.forename: Omar
authors.initials: O
authors.lastname: Dzaye
authors.affiliation: From the Cellular Neurosciences, Max Delbrück Center for Molecular Medicine (MDC), Berlin, Germany (ODaD, FH, VH, SAW, HK) ; Department of Neurosurgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, People's Republic of China (FH); Department of Neurology (KD, PE), Center for Stroke Research Berlin, Department of Experimental Neurology, Department of Neurology (PE, CH), Department of Neurology and Center for Anatomy, Institute of Cell Biology and Neurobiology (SL), Charité - Universitätsmedizin Berlin, Charitéplatz 1, Berlin, Germany; and Department of Neurosurgery, University of Schleswig-Holstein, Campus Kiel, Kiel, Germany (MS).
authors.forename: Feng
authors.initials: F
authors.lastname: Hu
authors.affiliation: From the Cellular Neurosciences, Max Delbrück Center for Molecular Medicine (MDC), Berlin, Germany (ODaD, FH, VH, SAW, HK) ; Department of Neurosurgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, People's Republic of China (FH); Department of Neurology (KD, PE), Center for Stroke Research Berlin, Department of Experimental Neurology, Department of Neurology (PE, CH), Department of Neurology and Center for Anatomy, Institute of Cell Biology and Neurobiology (SL), Charité - Universitätsmedizin Berlin, Charitéplatz 1, Berlin, Germany; and Department of Neurosurgery, University of Schleswig-Holstein, Campus Kiel, Kiel, Germany (MS).
authors.forename: Katja
authors.initials: K
authors.lastname: Derkow
authors.affiliation: From the Cellular Neurosciences, Max Delbrück Center for Molecular Medicine (MDC), Berlin, Germany (ODaD, FH, VH, SAW, HK) ; Department of Neurosurgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, People's Republic of China (FH); Department of Neurology (KD, PE), Center for Stroke Research Berlin, Department of Experimental Neurology, Department of Neurology (PE, CH), Department of Neurology and Center for Anatomy, Institute of Cell Biology and Neurobiology (SL), Charité - Universitätsmedizin Berlin, Charitéplatz 1, Berlin, Germany; and Department of Neurosurgery, University of Schleswig-Holstein, Campus Kiel, Kiel, Germany (MS).
authors.forename: Verena
authors.initials: V
authors.lastname: Haage
authors.affiliation: From the Cellular Neurosciences, Max Delbrück Center for Molecular Medicine (MDC), Berlin, Germany (ODaD, FH, VH, SAW, HK) ; Department of Neurosurgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, People's Republic of China (FH); Department of Neurology (KD, PE), Center for Stroke Research Berlin, Department of Experimental Neurology, Department of Neurology (PE, CH), Department of Neurology and Center for Anatomy, Institute of Cell Biology and Neurobiology (SL), Charité - Universitätsmedizin Berlin, Charitéplatz 1, Berlin, Germany; and Department of Neurosurgery, University of Schleswig-Holstein, Campus Kiel, Kiel, Germany (MS).
authors.forename: Philipp
authors.initials: P
authors.lastname: Euskirchen
authors.affiliation: From the Cellular Neurosciences, Max Delbrück Center for Molecular Medicine (MDC), Berlin, Germany (ODaD, FH, VH, SAW, HK) ; Department of Neurosurgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, People's Republic of China (FH); Department of Neurology (KD, PE), Center for Stroke Research Berlin, Department of Experimental Neurology, Department of Neurology (PE, CH), Department of Neurology and Center for Anatomy, Institute of Cell Biology and Neurobiology (SL), Charité - Universitätsmedizin Berlin, Charitéplatz 1, Berlin, Germany; and Department of Neurosurgery, University of Schleswig-Holstein, Campus Kiel, Kiel, Germany (MS).
authors.forename: Christoph
authors.initials: C
authors.lastname: Harms
authors.affiliation: From the Cellular Neurosciences, Max Delbrück Center for Molecular Medicine (MDC), Berlin, Germany (ODaD, FH, VH, SAW, HK) ; Department of Neurosurgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, People's Republic of China (FH); Department of Neurology (KD, PE), Center for Stroke Research Berlin, Department of Experimental Neurology, Department of Neurology (PE, CH), Department of Neurology and Center for Anatomy, Institute of Cell Biology and Neurobiology (SL), Charité - Universitätsmedizin Berlin, Charitéplatz 1, Berlin, Germany; and Department of Neurosurgery, University of Schleswig-Holstein, Campus Kiel, Kiel, Germany (MS).
authors.forename: Seija
authors.initials: S
authors.lastname: Lehnardt
authors.affiliation: From the Cellular Neurosciences, Max Delbrück Center for Molecular Medicine (MDC), Berlin, Germany (ODaD, FH, VH, SAW, HK) ; Department of Neurosurgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, People's Republic of China (FH); Department of Neurology (KD, PE), Center for Stroke Research Berlin, Department of Experimental Neurology, Department of Neurology (PE, CH), Department of Neurology and Center for Anatomy, Institute of Cell Biology and Neurobiology (SL), Charité - Universitätsmedizin Berlin, Charitéplatz 1, Berlin, Germany; and Department of Neurosurgery, University of Schleswig-Holstein, Campus Kiel, Kiel, Germany (MS).
authors.forename: Michael
authors.initials: M
authors.lastname: Synowitz
authors.affiliation: From the Cellular Neurosciences, Max Delbrück Center for Molecular Medicine (MDC), Berlin, Germany (ODaD, FH, VH, SAW, HK) ; Department of Neurosurgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, People's Republic of China (FH); Department of Neurology (KD, PE), Center for Stroke Research Berlin, Department of Experimental Neurology, Department of Neurology (PE, CH), Department of Neurology and Center for Anatomy, Institute of Cell Biology and Neurobiology (SL), Charité - Universitätsmedizin Berlin, Charitéplatz 1, Berlin, Germany; and Department of Neurosurgery, University of Schleswig-Holstein, Campus Kiel, Kiel, Germany (MS).
authors.forename: Susanne A
authors.initials: SA
authors.lastname: Wolf
authors.affiliation: From the Cellular Neurosciences, Max Delbrück Center for Molecular Medicine (MDC), Berlin, Germany (ODaD, FH, VH, SAW, HK) ; Department of Neurosurgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, People's Republic of China (FH); Department of Neurology (KD, PE), Center for Stroke Research Berlin, Department of Experimental Neurology, Department of Neurology (PE, CH), Department of Neurology and Center for Anatomy, Institute of Cell Biology and Neurobiology (SL), Charité - Universitätsmedizin Berlin, Charitéplatz 1, Berlin, Germany; and Department of Neurosurgery, University of Schleswig-Holstein, Campus Kiel, Kiel, Germany (MS).
authors.forename: Helmut
authors.initials: H
authors.lastname: Kettenmann
mesh_terms: D000818:Animals; D001921:Brain / Q000378:metabolism / Q000473:pathology; D001932:Brain Neoplasms / Q000378:metabolism* / Q000473:pathology; D045744:Cell Line, Tumor; D002645:Chickens; D005910:Glioma / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D015850:Interleukin-6 / Q000378:metabolism*; D008264:Macrophages / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D017628:Microglia / Q000378:metabolism* / Q000473:pathology; D014411:Neoplastic Stem Cells / Q000378:metabolism* / Q000473:pathology; D015398:Signal Transduction / Q000502:physiology; D051197:Toll-Like Receptor 4 / Q000096:biosynthesis*; D014407:Tumor Cells, Cultured; D015854:Up-Regulation / Q000502:physiology
chemical_list: C508600:IL6 protein, human; D015850:Interleukin-6; C495345:TLR4 protein, human; D051197:Toll-Like Receptor 4
keywords: Glioma; Glioma stem cells; Glioma-associated microglia/brain macrophages; IL-6; Toll-like receptor 4.