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*Molecular Immunology and Inflammation Branch, National Institute of Arthritis, Musculoskeletal and Skin Diseases, National Institutes of Health Bethesda, MD 20892;
The Division of Molecular Medicine, Walter and Eliza Hall Institute of Medical Research, Parkville, Australia;
The Department of Medical Biology, University of Melbourne, Parkville, Australia;
Laboratory of Mycobacterial Diseases and Cellular Immunology, Division of Bacterial, Parasitic, and Allergenic Products, Center for Biologics Evaluation and Research/U.S. Food and Drug Administration, Rockville, MD 20852;
¶Signal Transduction Laboratory, St Vincent’s Institute, Fitzroy, Australia; and
||Molecular Oncology Research Institute, Tufts-New England Medical Center, Boston, MA 02111
Tumor progression locus 2 (Tpl2, also known as Map3k8 and Cot) is a serine-threonine kinase critical in innate immunity, linking toll-like receptors (TLRs) to TNF production through its activation of ERK. Tpl2–/– macrophages have abrogated TNF production but overproduce IL-12 in response to TLR ligands. Despite enhanced IL-12 production, Tpl2–/– T cells have impaired IFN-
production. Therefore, the role of Tpl2 in a bona fide bacterial infection where all of these cytokines are important in host defense is unclear. To address this issue, we infected Tpl2–/– mice with the model pathogen Listeria monocytogenes. We found that Tpl2–/– mice infected i.v. with L. monocytogenes had increased pathogen burdens compared with wild-type mice and rapidly succumbed to infection. Enhanced susceptibility correlated with impaired signaling through TLR2 and nucleotide-binding oligomerization domain 2, two receptors previously shown to mediate Listeria recognition. Surprisingly, TNF production in response to infection was not significantly impaired, even though Tpl2 has been implicated in the regulation of TNF. We found that the role of Tpl2 has cell-type specific effects in regulating TNF and transduces signals from some, but not all, pattern recognition receptors (PRR). In contrast to the cell-type- and receptor-specific regulation of TNF, we found that Tpl2 is essential for IL-1β production from both macrophages and dendritic cells. These studies implicate Tpl2 as an important mediator for collaboration of pattern recognition receptors with danger-associated molecular patterns to induce TNF and IL-1β production and optimal host defense.
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
1 P.N.T. is supported by National Institutes of Health Grant R01 CA095431. W.T.W. is supported by National Institutes of Health Grant 1 K22 AR53953-01.
2 Address correspondence and reprint requests to Dr. Wendy Watford, Department of Infectious Diseases, College of Veterinary Medicine, University of Georgia, Athens, GA 30602. E-mail address: watfordw{at}uga.edu
3 Abbreviations used in this paper: PRR, pattern recognition receptor; DC, dendritic cell; Nod2, nucleotide-binding oligomerization domain 2; MDP, muramyl dipeptide; Tpl2, tumor progression locus 2; dectin-1, DC-associated C-type lectin 1; WT, wild type; LB, Luria broth; BMDC, bone marrow-derived DC; Pam3, Pam3CSK4; poly IC, polyinosine-polycytidylic acid; IBD, inflammatory bowel disease.
4 The online version of this article contains supplementary material.
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