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Infection and Immunity, May 2006, p. 2809-2816, Vol. 74, No. 5
0019-9567/06/$08.00+0     doi:10.1128/IAI.74.5.2809-2816.2006
Copyright © 2006, American Society for Microbiology. All Rights Reserved.

Toll-Like Receptor 2 Is Required for Inflammatory Responses to Francisella tularensis LVS

Jannet Katz,1,2 Ping Zhang,1 Michael Martin,1,{dagger} Stefanie N. Vogel,3 and Suzanne M. Michalek2*

Departments of Pediatric Dentistry,1 Microbiology, University of Alabama at Birmingham, Birmingham, Alabama 35294,2 Department of Microbiology and Immunology, University of Maryland—Baltimore, Baltimore, Maryland 212013

Received 25 January 2006/ Accepted 20 February 2006

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-{kappa}B 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-{kappa}B, 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-{kappa}B in modulating the inflammatory response.

* Corresponding author. Mailing address: Department of Microbiology, University of Alabama at Birmingham, 845 19th Street South, BBRB 258/5, Birmingham, AL 35294-2170. Phone: (205) 934-3470. Fax: (205) 934-1426. E-mail: suemich{at}uab.edu.

Editor: D. L. Burns

{dagger} Present address: Center for Oral Health and Systemic Disease, University of Louisville, Louisville, KY 40202.

Infection and Immunity, May 2006, p. 2809-2816, Vol. 74, No. 5
0019-9567/06/$08.00+0     doi:10.1128/IAI.74.5.2809-2816.2006
Copyright © 2006, American Society for Microbiology. All Rights Reserved.



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