Eosinophil-fibroblast interactions induce fibroblast IL-6 secretion and extracellular matrix gene expression: Implications in fibrogenesis
Eosinophil-fibroblast interactions induce fibroblast IL-6 secretion and extracellular matrix gene expression: Implications in fibrogenesis
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DOI：
10.1016/j.jaci.2005.06.031
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发表时间：
2005-10-01
影响因子：
14.2
通讯作者：
Ackerman, SJ
中科院分区：
文献类型：
--
作者：
Gomes, I;Mathur, SK;Ackerman, SJ
背景：嗜酸性粒细胞经常与过敏性疾病和其他疾病以及动物模型中的组织重塑和纤维化相关。嗜酸性粒细胞与成纤维细胞在组织重塑部位的紧密物理接近强烈暗示了它们在纤维发生中的作用，包括上皮下纤维化和哮喘的气道重塑特征。目的：鉴定嗜酸性粒细胞纤维化活性的介质并表征其机制。血嗜酸性粒细胞或嗜酸性粒细胞系与正常成纤维细胞的共培养系统被用来评估它们诱导成纤维细胞的能力表型，包括IL-6分泌和mRNA表达，以及诱导参与细胞外基质产生和稳态的基因。这些反应的介质被确定通过使用transwell屏障共培养，嗜酸性粒细胞条件培养基，和嗜酸性粒细胞特异性抗体neutralization.Results：嗜酸性粒细胞成纤维细胞共培养诱导有效的成纤维细胞IL-6分泌和mRNA表达，响应进一步增强IL-5。通过在渗透性transwell屏障存在下使用嗜酸性粒细胞-成纤维细胞共培养以及在嗜酸性粒细胞条件培养基中使用成纤维细胞培养，证明了嗜酸性粒细胞衍生介质的可溶性，表明不需要细胞接触。诱导成纤维细胞IL-6表达伴随着纤维连接蛋白和细胞外基质调节基因纤溶酶原激活物抑制剂1和金属蛋白酶组织抑制剂1的表达增加。抗体中和鉴定了成纤维细胞IL-6表达的主要嗜酸性粒细胞衍生介质为IL-1 β（> 60%），IL-1 α、IL-4和TGF-β的贡献较小（10%至20%）。嗜酸性粒细胞表达至少2种有效介质（IL-1 β和TGF-β），其诱导纤维化成纤维细胞表型，强烈支持嗜酸性粒细胞在嗜酸性粒细胞相关疾病中细胞外基质稳态失调和随后的组织重塑和纤维化中的作用。
Background: Eosinophils are frequently associated with tissue remodeling and fibrosis in allergic and other diseases and animal models. Their close physical proximity to fibroblasts at sites of tissue remodeling strongly implicates them in fibrogenesis, including subepithelial fibrosis and airway remodeling characteristic of asthma.Objective: To identify the mediators and characterize the mechanisms underlying the fibrogenic activities of eosinophils.Methods: A coculture system of blood eosinophils or eosinophil cell lines with normal fibroblasts was used to assess their ability to induce a fibrogenic fibroblast phenotype, including IL-6 secretion and mRNA expression, and induction of genes involved in extracellular matrix production and homeostasis. The mediators of these responses were identified by using transwell barrier cocultures, eosinophil-conditioned media, and cytokine-specific antibody neutralization.Results: Eosinophil-fibroblast coculture induced potent fibroblast IL-6 secretion and mRNA expression, responses further enhanced by IL-5. The soluble nature of the eosinophilderived mediators was demonstrated by using eosinophil-fibroblast coculture in the presence of permeable transwell barriers, and fibroblast culture in eosinophil-conditioned media, indicating that cell contact was not required. Induction of fibroblast IL-6 expression was accompanied by increased expression of fibronectin and the extracellular matrix regulatory genes plasminogen activator inhibitor 1 and tissue inhibitor of metalloproteinase 1. Antibody neutralization identified the principal eosinophil-derived mediator of fibroblast IL-6 expression as IL-1 beta (> 60%), with lesser contributions from IL-1 alpha, IL-4, and TGF-beta (10% to 20%).Conclusion: Eosinophils express at least 2 potent mediators (IL-1 beta and TGF-beta) that induce a fibrogenie fibroblast phenotype, strongly supporting a role for the eosinophil in the dysregulation of extracellular matrix homeostasis and consequent tissue remodeling and fibrosis in eosinophilassociated diseases.