过敏原刺激后气道中白细胞介素 6（IL-6）的增加和潜在的 IL-6 转导信号。
Increased IL-6 and Potential IL-6 trans-signalling in the airways after an allergen challenge.
机构信息
Department of Medicine, Division of Allergy, Pulmonary and Critical Care Medicine, the University of Wisconsin-Madison School of Medicine and Public Health, Madison, WI, USA.
Department of Pediatrics, University of Wisconsin School of Medicine and Public Health, Madison, WI, USA.
出版信息
Clin Exp Allergy. 2021 Apr;51(4):564-573. doi: 10.1111/cea.13832. Epub 2021 Feb 2.
BACKGROUND
In asthma, IL-6 is a potential cause of enhanced inflammation, tissue damage and airway dysfunction. IL-6 signalling is regulated by its receptor, which is composed of two proteins, IL-6R and GP130. In addition to their membrane form, these two proteins may be found as extracellular soluble forms. The interaction of IL-6 with soluble IL-6R (sIL-6R) can trigger IL-6 trans-signalling in cells lacking IL-6R. Conversely, the soluble form of GP130 (sGP130) competes with its membrane form to inhibit IL-6 trans-signalling.
OBJECTIVES
We aimed to analyse IL-6 trans-signalling proteins in the airways of subjects after an allergen challenge.
METHODS
We used a model of segmental bronchoprovocation with an allergen (SBP-Ag) in human subjects with allergy. Before and 48 h after SBP-Ag, bronchoalveolar lavages (BALs) allowed for the analysis of proteins in BAL fluids (BALFs) by ELISA, and membrane proteins on the surface of BAL cells by flow cytometry. In addition, we performed RNA sequencing (RNA-seq) and used proteomic data to further inform on the expression of the IL-6R subunits by eosinophils, bronchial epithelial cells and lung fibroblasts. Finally, we measured the effect of IL-6 trans-signalling on bronchial fibroblasts, in vitro.
RESULTS
IL-6, sIL-6R, sGP130 and the molar ratio of sIL-6R/sGP130 increased in the airways after SBP-Ag, suggesting the potential for enhanced IL-6 trans-signalling activity. BAL lymphocytes, monocytes and eosinophils displayed IL-6R on their surface and were all possible providers of sIL-6R, whereas GP130 was highly expressed in bronchial epithelial cells and lung fibroblasts. Finally, bronchial fibroblasts activated by IL-6 trans-signalling produced enhanced amounts of the chemokine, MCP-1 (CCL2).
CONCLUSION AND CLINICAL RELEVANCE
After a bronchial allergen challenge, we found augmentation of the elements of IL-6 trans-signalling. Allergen-induced IL-6 trans-signalling activity can activate fibroblasts to produce chemokines that can further enhance inflammation and lung dysfunction.
背景
在哮喘中，IL-6 是增强炎症、组织损伤和气道功能障碍的潜在原因。IL-6 信号由其受体调节，该受体由两种蛋白，IL-6R 和 GP130 组成。除了它们的膜形式外，这两种蛋白还可以作为细胞外可溶性形式存在。IL-6 与可溶性 IL-6R（sIL-6R）的相互作用可以在缺乏 IL-6R 的细胞中触发 IL-6 转导信号。相反，GP130 的可溶性形式（sGP130）与膜形式竞争以抑制 IL-6 转导信号。
目的
我们旨在分析过敏原刺激后气道中的 IL-6 转导蛋白。
方法
我们使用过敏原（SBP-Ag）分段支气管激发的模型在过敏的人类受试者中进行。在 SBP-Ag 之前和之后 48 小时，支气管肺泡灌洗（BAL）允许通过 ELISA 分析 BAL 液（BALF）中的蛋白质，以及通过流式细胞术分析 BAL 细胞表面的膜蛋白。此外，我们进行了 RNA 测序（RNA-seq），并使用蛋白质组学数据进一步告知嗜酸性粒细胞、支气管上皮细胞和肺成纤维细胞中 IL-6R 亚基的表达。最后，我们测量了 IL-6 转导信号对体外支气管成纤维细胞的影响。
结果
SBP-Ag 后，气道中 IL-6、sIL-6R、sGP130 和 sIL-6R/sGP130 的摩尔比增加，表明潜在的增强的 IL-6 转导信号活性。BAL 淋巴细胞、单核细胞和嗜酸性粒细胞表面均显示出 IL-6R，并且都是 sIL-6R 的可能提供者，而 GP130 则在支气管上皮细胞和肺成纤维细胞中高度表达。最后，被 IL-6 转导信号激活的支气管成纤维细胞产生了更多的趋化因子 MCP-1（CCL2）。
结论和临床相关性
在支气管过敏原挑战后，我们发现 IL-6 转导信号的元素增强。过敏原诱导的 IL-6 转导信号活性可以激活成纤维细胞产生趋化因子，从而进一步增强炎症和肺功能障碍。
Zotero 插件