title: Dose-dependent response of dendritic cells to 7-thia-8-oxo-guanosine and its modulation by polyinosinic:polycytidylic acid.
abstract: Targeting the endosomal Toll-like receptors (TLRs) by specific agonists seems to be a promising tool for stimulation of the immunogenicity of dendritic cells (DCs). Since the functional outcome upon the engagement of TLRs may be different, the aim of our study was to examine if and how different concentrations of 7-thia-8-oxo-guanosine (7-TOG), a selective TLR7 agonist, influence differentiation, maturation and functions of human monocyte-derived DCs (MoDCs) and if its effects on MoDCs could be modulated by co-ligation of TLR3. Immature MoDCs were treated with different concentrations of 7-TOG (25, 100 and 250 μmol/L) alone, or together with polyinosinic:polycytidylic acid, Poly (I:C) (10 ng/mL), a selective TLR3 agonist, for an additional 48 h. We showed that the highest concentration of 7-TOG stimulated the differentiation, maturation and allostimulatory capability of MoDCs. These changes were accompanied by an increased production of interleukin 12 (IL-12) and induction of T helper (Th)1 and Th17 immune responses. Both Th responses were significantly augmented by additional stimulation of MoDCs with Poly (I:C). The treatment of MoDCs with the intermediate concentration of 7-TOG resulted in the up-regulation of co-stimulatory molecule (CD86) and increased production of IL-1β and IL-6 by MoDCs, followed by the stimulation of the Th17 immune response. The lowest concentration of 7-TOG down-regulated the expression of CD40 on MoDCs and potentiated the Th2 immune response. The Th2 response was not significantly modulated by additional treatment of MoDCs with Poly (I:C), but this combination of TLR3/TLR7 agonists also stimulated both Th1 and Th17 responses. In conclusion, our results show that 7-TOG influences the phenotype and functions of MoDCs in a dose-dependent manner and suggests that fine-tuned signaling through TLR7 may be modified by the engagement of TLR3, resulting in a different outcome of immune response.
authors.affiliation: Medical Faculty of the Military Medical Academy, University of Defense in Belgrade, Crnotravska 17, 11002 Belgrade, Serbia.
authors.forename: Tanja
authors.initials: T
authors.lastname: Dzopalic
authors.forename: Ana
authors.initials: A
authors.lastname: Dragicevic
authors.forename: Biljana
authors.initials: B
authors.lastname: Bozic
authors.forename: Ivan
authors.initials: I
authors.lastname: Rajkovic
authors.forename: Miodrag
authors.initials: M
authors.lastname: Colic
mesh_terms: D002478:Cells, Cultured; D003713:Dendritic Cells / Q000166:cytology / Q000187:drug effects*; D004305:Dose-Response Relationship, Drug; D005434:Flow Cytometry; D006151:Guanosine / Q000031:analogs & derivatives* / Q000494:pharmacology; D006801:Humans; D007378:Interleukins / Q000378:metabolism; D007959:Lymphocyte Culture Test, Mixed; D011070:Poly I-C / Q000494:pharmacology*; D051193:Toll-Like Receptors / Q000819:agonists / Q000502:physiology
chemical_list: D007378:Interleukins; D051193:Toll-Like Receptors; D006151:Guanosine; C061136:isatoribine; D011070:Poly I-C