title: Tumor necrosis factor-α promotes survival and phenotypic maturation of poly(I:C)-treated dendritic cells but impairs their Th1 and Th17 polarizing capability.
abstract: OBJECTIVE
  Toll-like receptor (TLR)-3 synthetic agonist polyinosinic-polycytidylic acid (poly(I:C)) is a promising agent for dendritic cell (DC)-based anti-tumor vaccines because of its ability to induce a strong maturation of DCs, but such an effect is followed by stimulation of DC apoptosis. Tumor necrosis factor (TNF)-α may promote the survival of poly(I:C)-stimulated DCs, but it is not known in detail how this combination affects the maturation and polarization capacity of monocyte-derived (Mo)DCs.
  
  
  METHODS
  Immature MoDCs, generated from human monocytes, were treated with different concentrations of poly(I:C) combined with TNF-α, and the effect on survival, phenotype, production of cytokines, allostimulatory and Th polarization capacity was assessed after 24 and 48 h.
  
  
  RESULTS
  We showed that TNF-α inhibited the dose-dependent pro-apoptotic effect of poly(I:C). However, TNF-α also decreased poly(I:C)-induced production of interleukin (IL)-12 and IL-23 by MoDCs, which correlated with their diminished capacity to stimulate cellular proliferation, interferon-γ and IL-17 production by allogeneic CD4(+)T cells in co-culture. Such an effect was more pronounced after 24 h and could not be restored by CD40 ligation. In the presence of CD40L, TNF-α even stimulated IL-10 production and immunoglobulin-like transcript 3 expression by poly(I:C)-matured DCs, which correlated with their increased capacity to induce IL-10 production by CD4(+)T cells.
  
  
  CONCLUSIONS
  Even though TNF-α could promote the survival of poly(I:C)-matured MoDCs, it also suppresses key anti-tumor functions of these cells, which could have important implications when considering this, already suggested, protocol for the DC-based anti-tumor therapy.
authors.affiliation: Medical Faculty of the Military Medical Academy, University of Defense, Belgrade, Serbia.
authors.forename: Ana
authors.initials: A
authors.lastname: Thorne
authors.affiliation: Medical Faculty of the Military Medical Academy, University of Defense, Belgrade, Serbia.
authors.forename: Sergej
authors.initials: S
authors.lastname: Tomić
authors.affiliation: Faculty of Pharmacy, University of Belgrade, Belgrade, Serbia.
authors.forename: Bojan
authors.initials: B
authors.lastname: Pavlović
authors.affiliation: Medical Faculty of the Military Medical Academy, University of Defense, Belgrade, Serbia.
authors.forename: Dušan
authors.initials: D
authors.lastname: Mihajlović
authors.affiliation: Medical Faculty, University of Niš, Niš, Serbia.
authors.forename: Tanja
authors.initials: T
authors.lastname: Džopalić
authors.affiliation: Medical Faculty of the Military Medical Academy, University of Defense, Belgrade, Serbia; Medical Faculty, University of Niš, Niš, Serbia. Electronic address: fakultet.vma@mod.gov.rs.
authors.forename: Miodrag
authors.initials: M
authors.lastname: Čolić
mesh_terms: D017209:Apoptosis / Q000187:drug effects; D019013:CD40 Antigens / Q000378:metabolism; D023201:CD40 Ligand / Q000378:metabolism; D002454:Cell Differentiation / Q000187:drug effects*; D016764:Cell Polarity / Q000187:drug effects*; D002470:Cell Survival / Q000187:drug effects; D018920:Coculture Techniques; D003713:Dendritic Cells / Q000166:cytology* / Q000187:drug effects; D006801:Humans; D008562:Membrane Glycoproteins; D009000:Monocytes / Q000166:cytology; D010641:Phenotype; D011070:Poly I-C / Q000494:pharmacology*; D011956:Receptors, Cell Surface / Q000378:metabolism; D011971:Receptors, Immunologic; D018417:Th1 Cells / Q000166:cytology* / Q000187:drug effects; D058504:Th17 Cells / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*
chemical_list: D019013:CD40 Antigens; C107907:LILRB4 protein, human; D008562:Membrane Glycoproteins; D011956:Receptors, Cell Surface; D011971:Receptors, Immunologic; C439524:TNF protein, human; D014409:Tumor Necrosis Factor-alpha; D023201:CD40 Ligand; D011070:Poly I-C
keywords: DC-based tumor vaccines; TNF-α; Th-polarization; cytokines; dendritic cells; poly(I:C)