title: Hyaluronan carried by tumor-derived microvesicles induces IL-10 production in classical (CD14++CD16-) monocytes via PI3K/Akt/mTOR-dependent signalling pathway.
abstract: Tumor-derived microvesicles (TMV) can mimic effects of tumor cells leading to an increased anti-inflammatory cytokine production, such as interleukin 10 (IL-10), by tumor-infiltrating monocytes and macrophages. Yet, the mechanism of IL-10 induction by TMV in monocytes remains unclear. The co-incubation of TMV derived from the human pancreas carcinoma cell line (HPC-4) with human monocytes resulted in a nearly 30-fold increase in IL-10 protein production. This effect operates at the level of transcription since monocytes transduced with an adenovirus containing IL-10-promoter luciferase reporter gene showed a 5-fold induction of luciferase activity after treatment with TMV. Since tumor cells can express hyaluronan (HA), which participates in tumor invasion and metastases, we have tested its effect on IL-10 expression. We showed that HA at the concentration of 100μg/ml induces IL-10 protein expression and the IL-10 promoter activation in monocytes. Moreover, hyaluronidase treatment of TMV reduced IL-10 protein production by 50% and promoter activity by 40%. Inhibitors of the PI3K/Akt/mTOR pathway reduced both, TMV-induced IL-10 promoter activity and protein production, and the same was observed in monocytes when stimulated by HPC-4 cells or HA. Inhibition of PI3K activity down-regulated phosphorylation of the Akt and (to a lesser extent) mTOR proteins in monocytes following TMV or HA stimulation. When comparing monocyte subsets, TMV induced IL-10 protein and mRNA synthesis only in classical CD14++CD16-but not in CD16-positive monocytes. Our data show that TMV induce IL-10 synthesis in human classical monocytes via HA, which, in turn, activates the PI3K/Akt/mTOR pathway.
authors.affiliation: Department of Clinical Immunology, Polish-American Institute of Paediatrics, Jagiellonian University Medical College, Wielicka 265, 30-663 Krakow, Poland.
authors.forename: Marzena
authors.initials: M
authors.lastname: Lenart
authors.affiliation: Department of Clinical Immunology, Polish-American Institute of Paediatrics, Jagiellonian University Medical College, Wielicka 265, 30-663 Krakow, Poland.
authors.forename: Magdalena
authors.initials: M
authors.lastname: Rutkowska-Zapala
authors.affiliation: Department of Clinical Immunology, Polish-American Institute of Paediatrics, Jagiellonian University Medical College, Wielicka 265, 30-663 Krakow, Poland.
authors.forename: Monika
authors.initials: M
authors.lastname: Baj-Krzyworzeka
authors.affiliation: Department of Clinical Immunology, Polish-American Institute of Paediatrics, Jagiellonian University Medical College, Wielicka 265, 30-663 Krakow, Poland.
authors.forename: Rafał
authors.initials: R
authors.lastname: Szatanek
authors.affiliation: Department of Clinical Immunology, Polish-American Institute of Paediatrics, Jagiellonian University Medical College, Wielicka 265, 30-663 Krakow, Poland.
authors.forename: Kazimierz
authors.initials: K
authors.lastname: Węglarczyk
authors.affiliation: Centre for Translational Inflammation Research, School of Immunity and Infection, University of Birmingham, Edgbaston B15 2TT, United Kingdom.
authors.forename: Timothy
authors.initials: T
authors.lastname: Smallie
authors.affiliation: Asklepios-Fachklinik and Helmholtz Zentrum München, German Research Center for Environmental Health, Robert-Koch-Allee 1, D-82131, Gauting, Germany; Department of Infection, Immunity and Inflammation, University of Leicester, University Road, Leicester LE1 9HN, United Kingdom.
authors.forename: Löms
authors.initials: L
authors.lastname: Ziegler-Heitbrock
authors.affiliation: Department of Clinical Immunology, Polish-American Institute of Paediatrics, Jagiellonian University Medical College, Wielicka 265, 30-663 Krakow, Poland.
authors.forename: Marek
authors.initials: M
authors.lastname: Zembala
authors.affiliation: Department of Clinical Immunology, Polish-American Institute of Paediatrics, Jagiellonian University Medical College, Wielicka 265, 30-663 Krakow, Poland. Electronic address: misiedla@cyf-kr.edu.pl.
authors.forename: Maciej
authors.initials: M
authors.lastname: Siedlar
mesh_terms: D045744:Cell Line, Tumor; D055252:Cell-Derived Microparticles; D006801:Humans; D006820:Hyaluronic Acid / Q000008:administration & dosage*; D016753:Interleukin-10 / Q000096:biosynthesis*; D018950:Lipopolysaccharide Receptors / Q000378:metabolism; D008954:Models, Biological; D009000:Monocytes / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism*; D009369:Neoplasms / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D017452:Receptors, IgG / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects*; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism*
chemical_list: D006820:Hyaluronic Acid; D016753:Interleukin-10; D018950:Lipopolysaccharide Receptors; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; D017452:Receptors, IgG; D058570:TOR Serine-Threonine Kinases; C508609:IL10 protein, human
keywords: Hyaluronan; IL-10; Monocyte subsets; Monocytes; PI3K/Akt/mTOR pathway; Tumor-derived microvesicles,