Cot/tpl2 (MAP3K8) Mediates Myeloperoxidase Activity and Hypernociception following Peripheral Inflammation

Irene Soria-Castro, Agnieszka Krzyzanowska, Marta López Pelaéz, Javier Regadera, Gema Ferrer, Lluis Montoliu, Rosario Rodríguez-Ramos, Margarita Fernández, Susana Alemany

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    26 Citations (Scopus)


    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 TNFa, IL-1ß, and IL-6, as well as some chemokines such as MCP-1, MIP-1ß, 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, TNFa, and prostaglandin E2 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.
    Original languageEnglish
    Pages (from-to)33805-33815
    Number of pages11
    JournalJournal of Biological Chemistry
    Issue number44
    Publication statusPublished - 29 Oct 2010


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