title: Toll-like receptor 9 signaling can sensitize fibroblasts for apoptosis.
abstract: Toll-like receptors (TLR) are activated by microbial components and transmit signals that induce cell activation and differentiation. A number of recent reports further indicate that TLR also have the potential to induce apoptosis upon ligand binding. Here we investigate the apoptosis-inducing capacity of TLR9, the receptor for microbial CpG-DNA. Unlike ligands for TLR2 and TLR4, CpG-DNA failed to induce apoptosis in RAW264.7 mouse macrophages. In human embryonic kidney fibroblasts transfected stably to express TLR9, CpG-DNA weakly induced apoptosis in one clone but not others without an obvious allocation to differences in TLR-signaling events. Analysis of the apoptotic signaling showed that the mitochondrial pathway of apoptosis was triggered by TLR9, as mitochondrial Bax was activated upstream of caspase-cleavage. CpG-DNA-induced apoptosis was reduced by cycloheximide suggesting that de novo protein synthesis was required. Strikingly, stimulation with CpG-DNA resulted in a strongly increased sensitivity of TLR9-expressing fibroblasts to apoptosis induced by staurosporine and UV-irradiation. These results identify a mitochondrial pathway to apoptosis that can be triggered by TLR9 and that may serve to sensitize cells from the innate immune system to apoptosis in the course of an immune response.
authors.affiliation: Institute for Medical Microbiology, Immunology and Hygiene, Technische Universität München, Trogerstr. 9, D-81675 Munich, Germany.
authors.forename: Silke F
authors.initials: SF
authors.lastname: Fischer
authors.forename: Marc
authors.initials: M
authors.lastname: Rehm
authors.forename: Anette
authors.initials: A
authors.lastname: Bauer
authors.forename: Frederik
authors.initials: F
authors.lastname: Höfling
authors.forename: Susanne
authors.initials: S
authors.lastname: Kirschnek
authors.forename: Mark
authors.initials: M
authors.lastname: Rutz
authors.forename: Stefan
authors.initials: S
authors.lastname: Bauer
authors.forename: Hermann
authors.initials: H
authors.lastname: Wagner
authors.forename: Georg
authors.initials: G
authors.lastname: Häcker
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000235:genetics / Q000502:physiology*; D004268:DNA-Binding Proteins / Q000502:physiology*; D005347:Fibroblasts / Q000502:physiology*; D005786:Gene Expression Regulation / Q000502:physiology; D006801:Humans; D051379:Mice; D011956:Receptors, Cell Surface / Q000502:physiology*; D051217:Toll-Like Receptor 9
chemical_list: D004268:DNA-Binding Proteins; D011956:Receptors, Cell Surface; C495371:TLR9 protein, human; C495370:Tlr9 protein, mouse; D051217:Toll-Like Receptor 9