title: TLR9-independent effects of inhibitory oligonucleotides on macrophage responses to S. typhimurium.
abstract: Detection of bacterial CpG-containing DNA (CpG DNA) by innate immune cells is dependent on toll-like receptor 9 (TLR9). Here we show that the expression of tlr9 mRNA was induced in mouse bone marrow-derived macrophages (BMMs) upon infection with the facultative Gram-negative intracellular bacterium Salmonella enterica serovar Typhimurium (S. typhimurium). Treatment of BMM with the inhibitory oligonucleotide (ODN) 2114, an antagonist of TLR9 signalling, enhanced intracellular S. typhimurium numbers approximately fivefold, whereas a control ODN (2310) had no significant effect. Surprisingly, 2114 also amplified S. typhimurium bacterial loads in TLR9-deficient BMM. Indeed, 2114 suppressed responses (nuclear factor-kappaB-dependent reporter gene expression and interleukin-12p40 secretion) to not only CpG DNA, but also the TLR2 ligand Pam(3)Cys, in BMM and RAW264 cells in a sequence-specific manner. Inhibitory ODNs, which have been proposed as therapeutic agents for the treatment of systemic lupus erythematosus because of their inhibitory effects on TLR9 signalling, may thus compromise the host response to bacterial pathogens through TLR9-independent mechanisms.
authors.affiliation: The University of Queensland, Institute for Molecular Bioscience, Queensland, Australia.
authors.forename: Angela
authors.initials: A
authors.lastname: Trieu
authors.forename: Nilesh
authors.initials: N
authors.lastname: Bokil
authors.forename: Jasmyn A
authors.initials: JA
authors.lastname: Dunn
authors.forename: Tara L
authors.initials: TL
authors.lastname: Roberts
authors.forename: Damo
authors.initials: D
authors.lastname: Xu
authors.forename: Foo Y
authors.initials: FY
authors.lastname: Liew
authors.forename: David A
authors.initials: DA
authors.lastname: Hume
authors.forename: Katryn J
authors.initials: KJ
authors.lastname: Stacey
authors.forename: Matthew J
authors.initials: MJ
authors.lastname: Sweet
mesh_terms: D000818:Animals; D002460:Cell Line; D016173:Macrophage Colony-Stimulating Factor / Q000494:pharmacology; D008264:Macrophages / Q000187:drug effects* / Q000276:immunology / Q000382:microbiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009838:Oligodeoxyribonucleotides / Q000494:pharmacology*; D012480:Salmonella Infections / Q000276:immunology* / Q000382:microbiology; D012486:Salmonella typhimurium / Q000276:immunology*; D051217:Toll-Like Receptor 9 / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism
chemical_list: C408982:CPG-oligonucleotide; D009838:Oligodeoxyribonucleotides; D051217:Toll-Like Receptor 9; D016173:Macrophage Colony-Stimulating Factor