title: Release of IL-12 by dendritic cells activated by TLR ligation is dependent on MyD88 signaling, whereas TRIF signaling is indispensable for TLR synergy.
abstract: Recently, it has been shown that certain combinations of TLR ligands act in synergy to induce the release of IL-12 by DCs. In this study, we sought to define the critical parameters underlying TLR synergy. Our data show that TLR ligands act synergistically if MyD88- and TRIF-dependent ligands are combined. TLR4 uses both of these adaptor molecules, thus activation via TLR4 proved to be a synergistic event on its own. TLR synergy did not affect all aspects of DC activation but enhanced primarily the release of certain cytokines, particularly IL-12, whereas the expression of costimulatory molecules remained unchanged. Consequently, synergistic activation of DC did not affect their ability to induce T cell proliferation but resulted in T(H)1-biased responses in vitro and in vivo. Furthermore, we examined the impact of TLR ligand combinations on primary DC in vitro but observed only modest effects with a combination of CpG + Poly (I:C). However, noticeable synergy in terms of IL-12 production by DCs was detectable in vivo after systemic administration of CpG + Poly (I:C). Finally, we show that synergy is partially dependent on IFNAR signaling but does not require the release of IFNs to the enviroment, suggesting an autocrine action of type I IFNs.
authors.affiliation: Department of Dermatology, University of Mainz, Mainz, Germany. krummen@hautklinik.klinik.uni-mainz.de
authors.forename: Mathias
authors.initials: M
authors.lastname: Krummen
authors.forename: Sandra
authors.initials: S
authors.lastname: Balkow
authors.forename: Limei
authors.initials: L
authors.lastname: Shen
authors.forename: Stefanie
authors.initials: S
authors.lastname: Heinz
authors.forename: Carmen
authors.initials: C
authors.lastname: Loquai
authors.forename: Hans-Christian
authors.initials: HC
authors.lastname: Probst
authors.forename: Stephan
authors.initials: S
authors.lastname: Grabbe
mesh_terms: D033942:Adaptor Proteins, Vesicular Transport / Q000502:physiology*; D000818:Animals; D019013:CD40 Antigens / Q000502:physiology; D016764:Cell Polarity; D003713:Dendritic Cells / Q000276:immunology*; D007371:Interferon-gamma / Q000494:pharmacology; D018664:Interleukin-12 / Q000096:biosynthesis*; D008070:Lipopolysaccharides / Q000494:pharmacology; D008213:Lymphocyte Activation; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D053594:Myeloid Differentiation Factor 88 / Q000502:physiology*; D011070:Poly I-C / Q000494:pharmacology; D015398:Signal Transduction / Q000502:physiology*; D051193:Toll-Like Receptors / Q000502:physiology*
chemical_list: D033942:Adaptor Proteins, Vesicular Transport; D019013:CD40 Antigens; D007371:Interferon-gamma; D018664:Interleukin-12; D008070:Lipopolysaccharides; D053594:Myeloid Differentiation Factor 88; D011070:Poly I-C; D051193:Toll-Like Receptors; C507780:Myd88 protein, mouse; C476286:Ticam1 protein, mouse