title: Microenvironmental interleukin-6 suppresses toll-like receptor signaling in human leukemia cells through miR-17/19A.
abstract: The regulation of toll-like receptor (TLR) signaling in a tumor microenvironment is poorly understood despite its importance in cancer biology. To address this problem, TLR7-responses of chronic lymphocytic leukemia (CLL) cells were studied in the presence and absence of a human stromal cell-line derived from a leukemic spleen. CLL cells alone produced high levels of tumor necrosis factor (TNF)-α and proliferated in response to TLR7-agonists. A signal transducer and activator of transcription 3 -activating stromal factor, identified as interleukin (IL)-6, was found to upregulate microRNA (miR)-17 and miR-19a, target TLR7 and TNFA messenger RNA, and induce a state of tolerance to TLR7-agonists in CLL cells. Overexpression of the miR-17-92 cluster tolerized CLL cells directly and miR-17 and miR-19a antagomiRs restored TLR7-signaling. Inhibition of IL-6 signaling with antibodies or small-molecule Janus kinase inhibitors reversed tolerization and increased TLR7-stimulated CLL cell numbers in vitro and in NOD-SCIDγc (null) mice. These results suggest IL-6 can act as tumor suppressor in CLL by inhibiting TLR-signaling.
authors.affiliation: Biology Platform, Sunnybrook Research Institute, Toronto, Canada;
authors.forename: Yanmei
authors.initials: Y
authors.lastname: Li
authors.affiliation: Biology Platform, Sunnybrook Research Institute, Toronto, Canada;
authors.forename: Yonghong
authors.initials: Y
authors.lastname: Shi
authors.affiliation: Biology Platform, Sunnybrook Research Institute, Toronto, Canada;
authors.forename: Lindsay
authors.initials: L
authors.lastname: McCaw
authors.affiliation: Biology Platform, Sunnybrook Research Institute, Toronto, Canada; Department of Anatomy, Norman Bethune College of Medicine, Jilin University, Changchun, China;
authors.forename: You-Jun
authors.initials: YJ
authors.lastname: Li
authors.affiliation: Department of Immunology, University of Toronto, Toronto, Canada; Transplant Research Division, Toronto General Hospital, Toronto, Canada;
authors.forename: Fang
authors.initials: F
authors.lastname: Zhu
authors.affiliation: Department of Immunology, University of Toronto, Toronto, Canada; Transplant Research Division, Toronto General Hospital, Toronto, Canada;
authors.forename: Reg
authors.initials: R
authors.lastname: Gorczynski
authors.affiliation: Campbell Family Institute for Cancer Research, The Princess Margaret Cancer Centre, Toronto, Canada;
authors.forename: Gordon S
authors.initials: GS
authors.lastname: Duncan
authors.affiliation: Biology Platform, Sunnybrook Research Institute, Toronto, Canada; Department of Laboratory Medicine and Pathology, University of Toronto, Toronto, Canada;
authors.forename: Burton
authors.initials: B
authors.lastname: Yang
authors.affiliation: Division of Biology, The Key Laboratory of Chemistry for Natural Products of Guizhou Province and Chinese Academy of Sciences, Guiyang, China; and.
authors.forename: Yaacov
authors.initials: Y
authors.lastname: Ben-David
authors.affiliation: Biology Platform, Sunnybrook Research Institute, Toronto, Canada; Department of Immunology, University of Toronto, Toronto, Canada; Department of Medicine and Department of Medical Biophysics, University of Toronto, Toronto, Canada.
authors.forename: David E
authors.initials: DE
authors.lastname: Spaner
mesh_terms: D000818:Animals; D057134:Antibodies, Neutralizing / Q000494:pharmacology; D001402:B-Lymphocytes / Q000187:drug effects / Q000276:immunology* / Q000473:pathology; D045744:Cell Line, Tumor; D018920:Coculture Techniques; D015973:Gene Expression Regulation, Leukemic; D006801:Humans; D007108:Immune Tolerance; D015850:Interleukin-6 / Q000235:genetics / Q000276:immunology*; D053613:Janus Kinase 1 / Q000235:genetics / Q000276:immunology; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000235:genetics / Q000276:immunology / Q000473:pathology; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D035683:MicroRNAs / Q000235:genetics / Q000276:immunology*; D009841:Oligonucleotides / Q000494:pharmacology; D062085:RNA, Long Noncoding; D012333:RNA, Messenger / Q000235:genetics / Q000276:immunology; D050796:STAT3 Transcription Factor / Q000235:genetics / Q000276:immunology; D015398:Signal Transduction; D017154:Stromal Cells / Q000187:drug effects / Q000276:immunology* / Q000473:pathology; D051199:Toll-Like Receptor 7 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000276:immunology; D059016:Tumor Microenvironment; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis / Q000378:metabolism
chemical_list: D057134:Antibodies, Neutralizing; C508600:IL6 protein, human; D015850:Interleukin-6; C568997:MIR17HG, human; C524941:MIRN17 microRNA, human; C549214:MIRN19A microRNA, human; D035683:MicroRNAs; D009841:Oligonucleotides; D062085:RNA, Long Noncoding; D012333:RNA, Messenger; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; C495348:TLR7 protein, human; D051199:Toll-Like Receptor 7; D014409:Tumor Necrosis Factor-alpha; D053613:Janus Kinase 1