title: Etanercept impairs maturation of human monocyte-derived dendritic cells by inhibiting the autocrine TNFalpha-mediated signaling.
abstract: The success of anti-tumor necrosis factor alpha (TNFalpha) therapies has led to increased interest as to the mechanisms and consequences of TNFalpha blockade. The aim of the study was to examine the effects of TNFalpha blockade by etanercept on lipopolysaccharide (LPS) or peptidoglycan (PG)-induced maturation of human monocyte-derived dendritic cells (MDDCs). MDDCs grown from peripheral blood of healthy donors were stimulated by LPS or PG with/without the presence of etanercept. Concentrations of TNFalpha in cell supernatants were assessed by ELISA, while the cells were stained with monoclonal antibodies to CD83, CD80, CD86, CD11c, CD40, HLA-DR, and annexin-V and acquired using a flow cytometer. Etanercept significantly decreased the stimulated cell surface expression of HLA-DR, CD80, CD86, CD40 and CD83 on MDDCs in all examined samples. Etanercept in the same dose, but denatured to loss of specificity for TNFalpha, failed to change any of the aforementioned markers. In the presence of etanercept, concentrations of TNFalpha in cell supernatants were decreased by 53% on average, with a range of 25%-87%. Etanercept impaired the stimulated maturation of MDDCs by neutralizing the induced TNFalpha, produced by the same MDDCs after antigenic stimulation. The reported data confirms that TNFalpha blockade may have a direct effect on DCs, with a wide spectrum of potential secondary effects downstream. The data also suggests the presence of TNFalpha-mediated autocrine signaling, serving to accelerate or catalyze the maturation process of MDDCs.
authors.affiliation: Department of Internal Medicine A, Bnai Zion Medical Center, Ruth and Bruce Rappaport Faculty of Medicine, Technion, Haifa, Israel. gslobodin@yahoo.com
authors.forename: Gleb
authors.initials: G
authors.lastname: Slobodin
authors.forename: Aharon
authors.initials: A
authors.lastname: Kessel
authors.forename: Regina
authors.initials: R
authors.lastname: Peri
authors.forename: Natalia
authors.initials: N
authors.lastname: Zaigraikin
authors.forename: Michael
authors.initials: M
authors.lastname: Rozenbaum
authors.forename: Itzhak
authors.initials: I
authors.lastname: Rosner
authors.forename: Elias
authors.initials: E
authors.lastname: Toubi
mesh_terms: D000954:Antigens, Surface / Q000032:analysis; D019898:Autocrine Communication / Q000187:drug effects; D002478:Cells, Cultured; D003713:Dendritic Cells / Q000187:drug effects*; D000068800:Etanercept; D006801:Humans; D007074:Immunoglobulin G / Q000494:pharmacology*; D007155:Immunologic Factors; D008070:Lipopolysaccharides / Q000494:pharmacology; D009000:Monocytes / Q000166:cytology; D010457:Peptidoglycan / Q000494:pharmacology; D018124:Receptors, Tumor Necrosis Factor; D015398:Signal Transduction / Q000187:drug effects*; D014409:Tumor Necrosis Factor-alpha / Q000032:analysis / Q000037:antagonists & inhibitors* / Q000378:metabolism
chemical_list: D000954:Antigens, Surface; D007074:Immunoglobulin G; D007155:Immunologic Factors; D008070:Lipopolysaccharides; D010457:Peptidoglycan; D018124:Receptors, Tumor Necrosis Factor; D014409:Tumor Necrosis Factor-alpha; D000068800:Etanercept