Endogenous IL-17 as a mediator of neutrophil recruitment caused by endotoxin exposure in mouse airways
Endogenous IL-17 as a mediator of neutrophil recruitment caused by endotoxin exposure in mouse airways
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DOI：
10.4049/jimmunol.170.9.4665
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发表时间：
2003-05-01
影响因子：
4.4
通讯作者：
Lindén, A
中科院分区：
文献类型：
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作者：
Miyamoto, M;Prause, O;Lindén, A
我们之前已经证明，在大鼠气道中施用最近描述的细胞因子IL-17可以局部招募和激活中性粒细胞。在当前的研究中，我们研究了内源性IL-17是否参与介导小鼠气道内毒素暴露引起的中性粒细胞募集。我们的体内数据显示，局部内毒素暴露会在6小时后释放出游离的可溶性IL-17蛋白。在气道内毒素暴露后24小时，系统预处理中和性抗il -17 Ab几乎完全抑制中性粒细胞募集，但不能抑制6小时。中和抗il -6和抗巨噬细胞炎症蛋白(MIP)-2抗体预处理分别抑制局部内毒素暴露和IL-17引起的中性粒细胞募集。我们的体外数据显示，内毒素暴露分别刺激肺和脾T淋巴细胞中可溶性IL-17蛋白的释放，这种细胞因子的释放需要与气道巨噬细胞共培养。两种细胞共培养和刺激后，在脾脏T淋巴细胞中检测到细胞内IL-17蛋白，而在气道巨噬细胞中未检测到。最后，抗il -17不会改变内毒素诱导的T淋巴细胞和气道巨噬细胞IL-6和MIP-2的释放。总之，我们的研究结果表明，内毒素暴露导致T淋巴细胞释放IL-17，而这种细胞因子的释放需要巨噬细胞的存在。一旦释放，内源性IL-17的部分作用是诱导非淋巴细胞、非巨噬细胞局部释放中性粒细胞动员细胞因子，如IL-6和MIP-2，这有助于气道中性粒细胞的募集。这些与il -17相关的机制构成了针对气道疾病中性粒细胞过度募集的药物治疗的潜在靶点。
We have previously demonstrated that administration of the recently described cytokine IL-17 in rat airways in vivo recruits and activates neutrophils locally. In the current study, we examined whether endogenous IL-17 is involved in mediating neutrophil recruitment caused by endotoxin exposure in mouse airways. Our in vivo data show that local endotoxin exposure causes the release of free, soluble IL-17 protein 6 h later. Systemic pretreatment with a neutralizing anti-IL-17 Ab almost completely inhibits neutrophil recruitment 24 h, but not 6 h, after endotoxin exposure in the airways. Pretreatment with neutralizing anti-IL-6 and anti-macrophage inflammatory protein (MIP)-2 Abs inhibits neutrophil recruitment caused by local endotoxin exposure and IL-17, respectively. Our in vitro data show that endotoxin exposure stimulates the release of soluble IL-17 protein in T lymphocytes harvested from lung and spleen, respectively, and that this cytokine release requires coculture with airway macrophages. Intracellular IL-17 protein is detected in T lymphocytes from spleen but not in airway macrophages after coculture and stimulation of these two cell types. Finally, anti-IL-17 does not alter endotoxin-induced release of IL-6 and MIP-2 from T lymphocytes and airway macrophages in coculture. In conclusion, our results indicate that endotoxin exposure causes the release of IL-17 from T lymphocytes and that this cytokine release requires the presence of macrophages. Once released, endogenous IL-17 acts in part by inducing local release of neutrophil-mobilizing cytokines such as IL-6 and MIP-2, from nonlymphocyte, nonmacrophage cells, and this contributes to recruitment of neutrophils in the airways. These IL-17-related mechanisms constitute potential targets for pharmacotherapy against exaggerated neutrophil recruitment in airway disease.