title: Granulocyte colony-stimulating factor promotes the generation of regulatory DC through induction of IL-10 and IFN-alpha.
abstract: We have recently demonstrated that G-CSF promotes the generation of human T regulatory (T(REG)) type 1 cells. In this study, we investigated whether the immunomodulatory effects of G-CSF might be mediated by DC. CD14(+) monocytes were cultured with serum collected after clinical administration of G-CSF (post-G), which contained high amounts of IL-10 and IFN-alpha. Similar to incompletely matured DC, monocytes nurtured with post-G serum acquired a DC-like morphology, expressed high levels of costimulatory molecules and HLA-DR, and exhibited diminished IL-12p70 release and poor allostimulatory capacity. Importantly, post-G DC-like cells were insensitive to maturation stimuli. As shown by neutralization studies, IFN-alpha and, even more pronounced, IL-10 contained in post-G serum inhibited IL-12p70 release by post-G DC-like cells. Furthermore, phenotypic and functional features of post-G DC-like cells were replicated by culturing post-G monocytes with exogenous IL-10 and IFN-alpha. Post-G DC-like cells promoted Ag-specific hyporesponsiveness in naive allogeneic CD4(+) T cells and orchestrated a T(REG) response that was dependent on secreted TGF-beta 1 and IL-10. Finally, neutralization of IL-10 and IFN-alpha contained in post-G serum translated into abrogation of the regulatory features of post-G DC-like cells. This novel mechanism of immune regulation effected by G-CSF might be therapeutically exploited for tolerance induction in autoimmune disorders.
authors.affiliation: Department of Hematology, Laboratory of Immunology, Catholic University Medical School, Rome, Italy. sergiorutella@tin.it
authors.forename: Sergio
authors.initials: S
authors.lastname: Rutella
authors.forename: Giuseppina
authors.initials: G
authors.lastname: Bonanno
authors.forename: Luca
authors.initials: L
authors.lastname: Pierelli
authors.forename: Andrea
authors.initials: A
authors.lastname: Mariotti
authors.forename: Ettore
authors.initials: E
authors.lastname: Capoluongo
authors.forename: Anna Maria
authors.initials: AM
authors.lastname: Contemi
authors.forename: Franco
authors.initials: F
authors.lastname: Ameglio
authors.forename: Antonio
authors.initials: A
authors.lastname: Curti
authors.forename: Daniela G
authors.initials: DG
authors.lastname: De Ritis
authors.forename: Maria Teresa
authors.initials: MT
authors.lastname: Voso
authors.forename: Alessandro
authors.initials: A
authors.lastname: Perillo
authors.forename: Salvatore
authors.initials: S
authors.lastname: Mancuso
authors.forename: Giovanni
authors.initials: G
authors.lastname: Scambia
authors.forename: Roberto M
authors.initials: RM
authors.lastname: Lemoli
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Leone
mesh_terms: D000328:Adult; D000941:Antigens / Q000187:drug effects; D015496:CD4-Positive T-Lymphocytes / Q000187:drug effects; D018929:Cell Culture Techniques; D002454:Cell Differentiation / Q000187:drug effects*; D003713:Dendritic Cells / Q000187:drug effects*; D005260:Female; D016179:Granulocyte Colony-Stimulating Factor / Q000494:pharmacology*; D006801:Humans; D016898:Interferon-alpha / Q000096:biosynthesis* / Q000187:drug effects; D016753:Interleukin-10 / Q000096:biosynthesis*; D008297:Male; D009000:Monocytes / Q000187:drug effects; D044967:Serum
chemical_list: D000941:Antigens; D016898:Interferon-alpha; D016753:Interleukin-10; D016179:Granulocyte Colony-Stimulating Factor