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Infection and Immunity, March 2003, p. 1513-1519, Vol. 71, No. 3
0019-9567/03/$08.00+0     DOI: 10.1128/IAI.71.3.1513-1519.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.

Role of Toll-Like Receptor Signaling in the Apoptotic Response of Macrophages to Yersinia Infection

Yue Zhang and James B. Bliska*

Center for Infectious Diseases, Department of Molecular Genetics and Microbiology, State University of New York at Stony Brook, Stony Brook, New York 11794-5120

Received 23 September 2002/ Returned for modification 12 November 2002/ Accepted 29 November 2002

Macrophages encode several Toll-like receptors (TLRs) that recognize bacterial components, such as lipoproteins (TLR2) or lipopolysaccharides (TLR4), and activate multiple signaling pathways. Activation of transcription factor NF-{kappa}B by TLR2 or TLR4 signaling promotes proinflammatory and cell survival responses. Alternatively, TLR2 or TLR4 signaling can promote apoptosis if the activation of NF-{kappa}B is blocked. The gram-negative bacterial pathogen Yersinia pseudotuberculosis secretes into macrophages a protease (YopJ) that inhibits the activation of NF-{kappa}B and promotes apoptosis. We show that primary macrophages expressing constitutively active inhibitor {kappa}B kinase ß (IKKß) are completely resistant to YopJ-dependent apoptosis, indicating that YopJ inhibits signaling upstream of IKKß. Apoptosis is reduced two- to threefold in TLR4-/- macrophages infected with Y. pseudotuberculosis, while the apoptotic response of TLR2-/- macrophages to Y. pseudotuberculosis infection is equivalent to that of wild-type macrophages. Therefore, TLR4 is the primary source of apoptotic signaling in Yersinia-infected macrophages. Our results also show that a small percentage of macrophages can die as a result of an apoptotic process that is YopJ dependent but does not require TLR2 or TLR4 signaling.

* Corresponding author. Mailing address: Department of Molecular Genetics and Microbiology, Center for Infectious Diseases, SUNY Stony Brook, Stony Brook, NY 11794-5222. Phone: (631) 632-8782. Fax: (631) 632-4294. E-mail: jbliska{at}ms.cc.sunysb.edu.

Editor: D. L. Burns

Infection and Immunity, March 2003, p. 1513-1519, Vol. 71, No. 3
0019-9567/03/$08.00+0     DOI: 10.1128/IAI.71.3.1513-1519.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.



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