Cot/tpl2 (also known as MAP3K8) has emerged as a new and potentially interesting 
therapeutic anti-inflammatory target. Here, we report the first study of 
Cot/tpl2 involvement in acute peripheral inflammation in vivo. Six hours after 
an intraplantar injection of zymosan, Cot/tpl2(-/-) mice showed a 47% reduction 
in myeloperoxidase activity, concomitant with a 46% lower neutrophil recruitment 
and a 40% decreased luminol-mediated bioluminescence imaging in vivo. 
Accordingly, Cot/tpl2 deficiency provoked a 25-30% reduction in luminol-mediated 
bioluminescence and neutrophil recruitment together with a 65% lower macrophage 
recruitment 4 h following zymosan-induced peritonitis. Significantly impaired 
levels of G-CSF and GM-CSF and of other cytokines such as TNFα, IL-1β, and IL-6, 
as well as some chemokines such as MCP-1, MIP-1β, and keratinocyte-derived 
chemokine, were detected during the acute zymosan-induced intraplantar 
inflammatory response in Cot/tpl2(-/-) mice. Moreover, Cot/tpl2 deficiency 
dramatically decreased the production of the hypernociceptive ligand NGF at the 
inflammatory site during the course of inflammation. Most importantly, Cot/tpl2 
deficiency significantly reduced zymosan-induced inflammatory hypernociception 
in mice, with a most pronounced effect of a 50% decrease compared with wild type 
(WT) at 24 h following intraplantar injection of zymosan. At this time, 
Cot/tpl2(-/-) mice showed significantly reduced NGF, TNFα, and prostaglandin 
E(2) levels compared with WT littermates. In conclusion, our study demonstrates 
an important role of Cot/tpl2 in the NGF, G-CSF, and GM-CSF production and 
myeloperoxidase activity in the acute inflammatory response process and its 
implication in inflammatory hypernociception.