title: Activated human hepatic stellate cells induce myeloid derived suppressor cells from peripheral blood monocytes in a CD44-dependent fashion.
abstract: OBJECTIVE
  Myeloid derived suppressor cells (MDSCs) are a heterogeneous population of cells associated with the suppression of immunity. However, little is known about how or where MDSCs are induced and from which cells they originate. The liver is known for its immune regulatory functions. Here, we investigated the capacity of human hepatic stellate cells (HSCs) to transform peripheral blood monocytes into MDSCs.
  
  
  METHODS
  We cultured freshly isolated human monocytes from healthy donors on primary human HSCs or an HSC cell-line and characterized the phenotype and function of resulting CD14(+)HLA-DR(-/low) monocytes by flow cytometry, quantitative PCR, and functional assays. We analyzed the molecular mechanisms underlying the induction and function of the CD14(+)HLA-DR(-/low) cells by using blocking antibodies or knock-down technology.
  
  
  RESULTS
  Mature peripheral blood monocytes co-cultured with HSCs downregulated HLA-DR and developed a phenotypic and functional profile similar to MDSCs. Only activated but not freshly isolated HSCs were capable of inducing CD14(+)HLA-DR(-/low) cells. Such CD14(+)HLA-DR(-/low) monocyte-derived MDSCs suppressed T-cell proliferation in an arginase-1 dependent fashion. HSC-induced development of CD14(+)HLA-DR(-/low) monocyte-derived MDSCs was not mediated by soluble factors, but required physical interaction and was abrogated by blocking CD44.
  
  
  CONCLUSIONS
  Our study shows that activated human HSCs convert mature peripheral blood monocytes into MDSCs. As HSCs are activated during chronic inflammation, the subsequent local induction of MDSCs may prevent ensuing excessive liver injury. HSC-induced MDSCs functionally and phenotypically resemble those isolated from liver cancer patients. Thus, our data suggest that local generation of MDSCs by liver-resident HSCs may contribute to immune suppression during inflammation and cancer in the liver.
authors.affiliation: Institutes of Molecular Medicine and Experimental Immunology, University of Bonn, Germany. B.Hoechst@gmail.com
authors.forename: Bastian
authors.initials: B
authors.lastname: Höchst
authors.forename: Frank A
authors.initials: FA
authors.lastname: Schildberg
authors.forename: Pia
authors.initials: P
authors.lastname: Sauerborn
authors.forename: Yvonne A
authors.initials: YA
authors.lastname: Gäbel
authors.forename: Heidrun
authors.initials: H
authors.lastname: Gevensleben
authors.forename: Diane
authors.initials: D
authors.lastname: Goltz
authors.forename: Lukas C
authors.initials: LC
authors.lastname: Heukamp
authors.forename: Andreas
authors.initials: A
authors.lastname: Türler
authors.forename: Matthias
authors.initials: M
authors.lastname: Ballmaier
authors.forename: Friederike
authors.initials: F
authors.lastname: Gieseke
authors.forename: Ingo
authors.initials: I
authors.lastname: Müller
authors.forename: Jörg
authors.initials: J
authors.lastname: Kalff
authors.forename: Christian
authors.initials: C
authors.lastname: Kurts
authors.forename: Percy A
authors.initials: PA
authors.lastname: Knolle
authors.forename: Linda
authors.initials: L
authors.lastname: Diehl
mesh_terms: D001119:Arginase / Q000037:antagonists & inhibitors / Q000378:metabolism; D002450:Cell Communication / Q000276:immunology; D002454:Cell Differentiation / Q000276:immunology; D002460:Cell Line; D049109:Cell Proliferation / Q000187:drug effects; D018920:Coculture Techniques; D015536:Down-Regulation; D006684:HLA-DR Antigens / Q000378:metabolism; D055166:Hepatic Stellate Cells / Q000276:immunology*; D006801:Humans; D018960:Hyaluronan Receptors / Q000378:metabolism*; D007108:Immune Tolerance; D018950:Lipopolysaccharide Receptors / Q000378:metabolism; D008213:Lymphocyte Activation; D009000:Monocytes / Q000166:cytology* / Q000276:immunology*; D022423:Myeloid Cells / Q000166:cytology* / Q000276:immunology*; D013601:T-Lymphocytes / Q000166:cytology / Q000187:drug effects / Q000276:immunology
chemical_list: C497483:CD44 protein, human; D006684:HLA-DR Antigens; D018960:Hyaluronan Receptors; D018950:Lipopolysaccharide Receptors; C574619:ARG1 protein, human; D001119:Arginase
keywords: Arginase; CD44; HSC; Hepatic stellate cell; IFN; MDSC; Myeloid derived suppressor cell; PGE(2); SCF; VEGF; hepatic stellate cell; interferon; myeloid derived suppressor cell; prostaglandin E(2); shRNA; siRNA; small hairpin RNA; small interfering RNA; stem cell factor; vascular endothelial growth factor