Toll-Like Receptor 2 Is Required for Inflammatory Responses toFrancisella tularensisLVS

Abstract

ABSTRACTFrancisella tularensis, a gram-negative bacterium, is the etiologic agent of tularemia and has recently been classified as a category A bioterrorism agent. Infections withF. tularensisresult 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 toF. tularensisLVS, and the role of NF-κB in regulating these responses. Stimulation of bone marrow-derived dendritic cells from C57BL/6 wild-type (wt) and TLR4−/−but not TLR2−/−mice, with liveF. tularensisLVS elicited a dose-dependent increase in the production of tumor necrosis factor alpha.F. tularensisLVS 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 toF. tularensisLVS, indicating that the functional heterodimer is TLR2/TLR6. Stimulation of dendritic cells withF. tularensisresulted in the activation of NF-κB, 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 toF. tularensisLVS in vitro and the regulatory function of NF-κB in modulating the inflammatory response.