Instituto de Investigaciones Biomédicas Alberto Sols, Consejo Superior de Investigaciones Cientificas-Universidad Autónoma de Madrid, Madrid 28029.
J Biol Chem. 2010 Oct 29;285(44):33805-15. doi: 10.1074/jbc.M110.169409. Epub 2010 Aug 24.
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.
Cot/tpl2（也称为 MAP3K8）已成为新的、具有潜在治疗意义的抗炎靶点。在这里，我们首次报道了 Cot/tpl2 在体内急性外周炎症中的作用。在足垫注射酵母聚糖后 6 小时，Cot/tpl2（-/-）小鼠的髓过氧化物酶活性降低了 47%，同时中性粒细胞募集减少了 46%，体内发光氨介导的生物发光成像减少了 40%。因此，Cot/tpl2 缺乏导致酵母聚糖诱导腹膜炎 4 小时后发光氨介导的生物发光和中性粒细胞募集减少 25-30%，同时巨噬细胞募集减少 65%。在 Cot/tpl2（-/-）小鼠的急性酵母聚糖诱导的足垫炎症反应中，检测到 G-CSF 和 GM-CSF 以及其他细胞因子（如 TNFα、IL-1β 和 IL-6）和一些趋化因子（如 MCP-1、MIP-1β 和角质细胞衍生趋化因子）水平显著降低。此外，Cot/tpl2 缺乏可显著降低炎症部位神经生长因子（NGF）的产生。最重要的是，Cot/tpl2 缺乏可显著降低酵母聚糖诱导的炎症性痛觉过敏，与野生型（WT）相比，在酵母聚糖注射后 24 小时内，痛觉过敏降低了 50%。此时，与 WT 同窝仔鼠相比，Cot/tpl2（-/-）小鼠的 NGF、TNFα 和前列腺素 E2（PGE2）水平明显降低。综上所述，我们的研究表明 Cot/tpl2 在急性炎症反应过程中对 NGF、G-CSF 和 GM-CSF 的产生以及髓过氧化物酶活性具有重要作用，并与炎症性痛觉过敏有关。
