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-gamma 
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-1beta 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-1beta production and optimal host defense.