Molecular mechanisms of cytokine and chemokine release from eosinophils activated by IL-17A, IL-17F, and IL-23: Implication for Th17 lymphocytes-mediated allergic inflammation
Molecular mechanisms of cytokine and chemokine release from eosinophils activated by IL-17A, IL-17F, and IL-23: Implication for Th17 lymphocytes-mediated allergic inflammation
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DOI：
10.4049/jimmunol.180.8.5625
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发表时间：
2008-04-15
影响因子：
4.4
通讯作者：
Lam, Christopher W. K.
中科院分区：
文献类型：
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作者：
Cheung, Phyllis F. Y.;Wong, Chun K.;Lam, Christopher W. K.
IL-17A和IL-17F是IL-17家族的成员，在过敏性炎症中起着至关重要的作用。最近的研究报道，IL-17A和IL-17F的产生来自一个不同的Th淋巴细胞亚群Th17，特异性地被IL-23诱导，IL-23是树突状细胞和巨噬细胞对微生物刺激的反应。因此，IL-23-IL-17轴可能在感染和过敏性疾病之间提供了联系。在本研究中，我们研究了IL-17A、IL-17F和IL-23单独或联合作用对嗜酸性粒细胞释放细胞因子和趋化因子的影响及其潜在的细胞内机制。发现人嗜酸性粒细胞在蛋白水平上组成性地表达IL-17A、IL-17F和IL-23受体。IL-17A、IL-17F和IL-23可以诱导嗜酸性粒细胞释放趋化因子gro - α /CXCL1、IL-8/CXCL8和MIP-1 β /CCL4， IL-17F和IL-23还可以增加促炎细胞因子IL-1 β和IL-6的产生。IL-17F和IL-23联合治疗对促炎细胞因子的释放有协同作用，且IL-23对促炎细胞因子的释放有剂量依赖性增强作用，而IL-17F对促炎细胞因子的释放无剂量依赖性。进一步的研究表明，IL-17A、IL-17F和IL-23不同程度地激活了ERK、p38 MAPK和NF-kappa B通路。此外，使用选择性抑制剂抑制这些途径可以显著消除IL-17A、IL-17F和IL-23诱导的趋化因子释放，以及IL-17F和IL-23联合处理介导的IL-1 β和IL-6产生的协同增加。综上所述，我们的研究结果为在过敏性炎症中Th17淋巴细胞通过细胞内信号级联的差异介导嗜酸性粒细胞的激活提供了见解。
IL-17A and IL-17F are members of the IL-17 family that play crucial roles in allergic inflammation. Recent studies reported that IL-17A and IL-17F production from a distinct Th lymphocyte subset, Th17, was specifically induced by IL-23, which was produced by dendritic cells and macrophages in response to microbial stimuli. The IL-23-IL-17 axis might therefore provide a link between infections and allergic diseases. In the present study, we investigated the effects of IL-17A, IL-17F, and IL-23, alone or in combination, on cytokine and chemokine release from eosinophils and the underlying intracellular mechanisms. Human eosinophils were found to constitutively express receptors for IL-17A, IL-17F, and IL-23 at the protein level. IL-17A, IL-17F, and IL-23 could induce the release of chemokines GRO-alpha/CXCL1, IL-8/CXCL8, and MIP-1 beta/CCL4 from eosinophils, while IL-17F and IL-23 could also increase the production of proinflammatory cytokines IL-1 beta and IL-6. Synergistic effects were observed in the combined treatment of IL-17F and IL-23 on the release of proinflammatory cytokines, and the effects were dose-dependently enhanced by IL-23, but not IL-17F. Further investigations showed that IL-17A, IL-17F, and IL-23 differentially activated the ERK, p38 MAPK, and NF-kappa B pathways. Moreover, inhibition of these pathways using selective inhibitors could significantly abolish the chemokine release induced by IL-17A, IL-17F, and IL-23 and the synergistic increases on IL-1 beta and IL-6 production mediated by combined treatment of IL-17F and IL-23. Taken together, our findings provide insight for the Th17 lymphocyte-mediated activation of eosinophils via differential intracellular signaling cascades in allergic inflammation.