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 luminolmediated 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 TNF␣, IL-1, and IL-6, as well as some chemokines such as MCP-1, MIP-1, 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, TNF␣, 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. 2). Cot/tpl2, also known as MAP3K8, is the sole MAP3K that activates the MKK1/ 2-ERK1/2 pathway in response to stimulation of the TLR/IL-1 receptor superfamily, as well as in response to the activation of some receptors of the TNF family (3-10). However, Cot/tpl2 does not participate in the activation of ERK1/2 by stimulation of the C-type lectin receptor dectin-1 (11). In resting cells, Cot/tpl-2 forms a stable and inactive complex with p105 NF-B and ABIN2 (A20-binding inhibitor of NF-B2), among other proteins, to protect Cot/tpl-2 from degradation. Adequate TLR/IL-1 receptor stimulation induces the activation of the IKK complex; active IKK kinase phosphorylates p105 NF-B, triggering its partial degradation to p50 NF-B (12-15). Cot/tpl2 is then dissociated from the complex and with an adequate phosphorylation state (16 -19) is capable of activating MKK1 and consequently ERK1/2 (6, 20 -22) prior to being rapidly degraded through the proteasome pathway (6,20,23). Cot/tpl2 is required to process pre-TNF␣ to its mature secreted form in LPS-stimulated macrophages (24). In addition, in different isolated cell types Cot/tpl2 controls the secretion of other cytokines and chemokines such as IL-8, MCP-1, MIP-1, KC,10,[24][25][26][27]. Moreover, Cot/tpl2 activation is necessary for the production of PGE 2 ...
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