title: Toll-like receptor 2 is required for inflammatory responses to Francisella tularensis LVS.
abstract: Francisella tularensis, a gram-negative bacterium, is the etiologic agent of tularemia and has recently been classified as a category A bioterrorism agent. Infections with F. tularensis result in an inflammatory response that plays an important role in the pathogenesis of the disease; however, the cellular mechanisms mediating this response have not been completely elucidated. In the present study, we determined the role of Toll-like receptors (TLRs) in mediating inflammatory responses to F. tularensis LVS, and the role of NF-kappaB in regulating these responses. Stimulation of bone marrow-derived dendritic cells from C57BL/6 wild-type (wt) and TLR4-/- but not TLR2-/- mice, with live F. tularensis LVS elicited a dose-dependent increase in the production of tumor necrosis factor alpha. F. tularensis LVS also induced in a dose-dependent manner an up-regulation in the expression of the costimulatory molecules CD80 and CD86 and of CD40 and the major histocompatibility complex class II molecules on dendritic cells from wt and TLR4-/- but not TLR2-/- mice. TLR6, not TLR1, was shown to be involved in mediating the inflammatory response to F. tularensis LVS, indicating that the functional heterodimer is TLR2/TLR6. Stimulation of dendritic cells with F. tularensis resulted in the activation of NF-kappaB, which resulted in a differential effect on the production of pro- and anti-inflammatory cytokines. Taken together, our results demonstrate the role of TLR2/TLR6 in the host's inflammatory response to F. tularensis LVS in vitro and the regulatory function of NF-kappaB in modulating the inflammatory response.
authors.affiliation: Department of Pediatric Dentistry, University of Alabama at Birmingham, Birmingham, AL 35294, USA.
authors.forename: Jannet
authors.initials: J
authors.lastname: Katz
authors.forename: Ping
authors.initials: P
authors.lastname: Zhang
authors.forename: Michael
authors.initials: M
authors.lastname: Martin
authors.forename: Stefanie N
authors.initials: SN
authors.lastname: Vogel
authors.forename: Suzanne M
authors.initials: SM
authors.lastname: Michalek
mesh_terms: D000818:Animals; D018122:B7-1 Antigen / Q000032:analysis; D051940:B7-2 Antigen / Q000032:analysis; D019013:CD40 Antigens / Q000032:analysis; D005604:Francisella tularensis / Q000276:immunology*; D007249:Inflammation / Q000209:etiology*; D016753:Interleukin-10 / Q000096:biosynthesis; D051379:Mice; D008810:Mice, Inbred C57BL; D016328:NF-kappa B / Q000502:physiology; D051194:Toll-Like Receptor 1 / Q000502:physiology; D051195:Toll-Like Receptor 2 / Q000502:physiology*; D051197:Toll-Like Receptor 4 / Q000502:physiology; D051216:Toll-Like Receptor 6 / Q000502:physiology; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis
chemical_list: D018122:B7-1 Antigen; D051940:B7-2 Antigen; D019013:CD40 Antigens; C497965:Cd86 protein, mouse; D016328:NF-kappa B; C493486:Tlr2 protein, mouse; C493487:Tlr4 protein, mouse; C495369:Tlr6 protein, mouse; D051194:Toll-Like Receptor 1; D051195:Toll-Like Receptor 2; D051197:Toll-Like Receptor 4; D051216:Toll-Like Receptor 6; D014409:Tumor Necrosis Factor-alpha; D016753:Interleukin-10