BACKGROUND AND PURPOSE:IL-33 signals through ST2 receptors and induces adaptive and innate inflammation. IL-33/ST2 is involved in adaptive inflammation-induced pain. Here, we have investigated the contribution of IL-33/ST2-triggered mechanisms to carrageenin-induced innate inflammation. EXPERIMENTAL APPROACH:Carrageenin- and IL-33-induced inflammatory responses were assessed in BALB/c- (WT) and ST2-deficient ((-/-) ) mice as follows: oedema (plethysmometer), myeloperoxidase activity (colorimetric assay), mechanical hyperalgesia (electronic version of von Frey filaments), cytokine levels (ELISA), PGE2 (RIA), mRNA expression (quantitative PCR), drug treatments targeting leukocyte recruitment (fucoidin), TNF-α (infliximab), CXCL1 (antibody to CXCL1), IL-1 (IL-1ra), endothelin ETA (clazosentan) and ETB (BQ788) receptors and COX (indomethacin). KEY RESULTS:Carrageenin injection increased ST2 and IL-33 mRNA expression and IL-33 production in paw skin samples. Carrageenin-induced paw oedema, hyperalgesia and myeloperoxidase activity were reduced in ST2(-/-) compared with WT mice, effects mimicked by IL-33 injection in the paw. Furthermore, IL-33-induced hyperalgesia was reduced by fucoidin suggesting a role for recruited leukocytes in its hyperalgesic effect. IL-33-induced hyperalgesia in naïve mice was reduced by treatments targeting TNF, CXCL1, IL-1, endothelin receptors and COX while carrageenin-induced ST2-dependent TNF-α, CXCL1, IL-1β, IL-10 and PGE2 production and preproET-1 mRNA expression. Combining IL-33 and carrageenin at doses that were ineffective as single treatment induced significant hyperalgesia, oedema, myeloperoxidase activity and cytokine production in a ST2-dependent manner. CONCLUSIONS AND IMPLICATIONS:IL-33/ST2 signalling triggers the production of inflammatory mediators contributing to carrageenin-induced inflammation. These data reinforces the importance of IL-33/ST2 signalling as a target in innate inflammation and inflammatory pain.

译文

背景与目的:IL-33通过ST2受体发出信号,并诱导适应性和先天性炎症。 IL-33 / ST2与适应性炎症引起的疼痛有关。在这里,我们调查了IL-33 / ST2触发机制对角叉菜胶诱导的先天性炎症的贡献。
实验方法:角叉菜胶和IL-33诱导的炎症反应在BALB / c-(WT)和ST2缺乏((-/-))小鼠中进行了如下评估:水肿(体积描记器),髓过氧化物酶活性(比色测定),机械性痛觉过敏(von Frey细丝的电子版本),细胞因子水平(ELISA),PGE2(RIA),mRNA表达(定量PCR),靶向白细胞募集的药物(岩藻糖蛋白),TNF-α(英夫利昔单抗),CXCL1(CXCL1抗体) ),IL-1(IL-1ra),内皮素ETA(clazosentan)和ETB(BQ788)受体以及COX(吲哚美辛)。
关键结果:角叉菜胶注射液可增加爪皮肤样品中ST2和IL-33 mRNA的表达以及IL-33的产生。与野生型小鼠相比,角叉菜胶诱导的爪水肿,痛觉过敏和髓过氧化物酶活性在ST2(-/-)中降低,这种作用与在爪中注射IL-33相似。此外,岩藻糖苷可降低IL-33诱导的痛觉过敏,提示募集的白细胞在其痛觉过敏作用中起作用。通过针对TNF,CXCL1,IL-1,内皮素受体和COX的治疗,IL-33诱导的单纯性痛觉过敏减少,而角叉菜胶诱导的ST2依赖性TNF-α,CXCL1,IL-1β,IL-10和PGE2的产生以及preproET-1 mRNA表达。以单次治疗无效的剂量将IL-33和角叉菜胶组合以ST2依赖性方式诱导明显的痛觉过敏,水肿,髓过氧化物酶活性和细胞因子产生。
结论和意义:IL-33 / ST2信号会触发炎症介质的产生,从而导致角叉菜胶引起的炎症。这些数据加强了IL-33 / ST2信号作为先天性炎症和炎性疼痛中靶标的重要性。

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