The TNF Family Molecules LIGHT and Lymphotoxin αβ Induce a Distinct Steroid-Resistant Inflammatory Phenotype in Human Lung Epithelial Cells.
The TNF Family Molecules LIGHT and Lymphotoxin αβ Induce a Distinct Steroid-Resistant Inflammatory Phenotype in Human Lung Epithelial Cells.
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DOI：
10.4049/jimmunol.1500356
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发表时间：
2015-09-01
期刊：
影响因子：
--
通讯作者：
Croft M
中科院分区：
文献类型：
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作者：
da Silva Antunes R;Madge L;Soroosh P;Tocker J;Croft M
肺上皮细胞被认为是导致哮喘等疾病的炎症分子和细胞外基质蛋白的重要来源。了解刺激上皮细胞的因素可能会给控制肺部炎症带来新的见解。本研究旨在探讨人肺上皮细胞对 TNF 家族分子 LIGHT 和淋巴毒素 αβ (LTαβ) 的反应性。用 LIGHT 和 LTαβ 刺激支气管和肺泡上皮细胞系以及原代人支气管上皮细胞，并测量炎症细胞因子和趋化因子的表达以及上皮间质转化和纤维化/重塑的标记物。 LTβR 是 LIGHT 和 LTαβ 共有的受体，在所有上皮细胞上组成型表达。相应地，LIGHT和LTαβ在所有测试的上皮细胞中强烈诱导一组有限但高度独特的炎症基因，即粘附分子ICAM-1和VCAM-1； [0100] 趋化因子CCL5、CCL20、CXCL1、CXCL3、CXCL5和CXCL11；细胞因子 IL-6、激活素 A 和 GM-CSF；以及金属蛋白酶 MMP-9 和 ADAM-8。重要的是，大多数炎症分子的诱导对皮质类固醇布地奈德的抑制作用不敏感。 LIGHT 和 LTαβ 还适度下调 E-钙粘蛋白（一种与维持上皮完整性相关的蛋白质），但不会显着促进细胞外基质蛋白或 α-平滑肌肌动蛋白的产生。因此，LIGHT 和 LTαβ 通过组成型表达的 LTβR 在气道上皮细胞中诱导独特的类固醇抗性炎症特征。这些发现支持了我们之前的小鼠研究，即 LIGHT 和 LTαβ 受体有助于哮喘和特发性肺纤维化特征性肺部炎症的发展。
Lung epithelial cells are considered important sources of inflammatory molecules and extracellular matrix proteins that contribute to diseases such as asthma. Understanding the factors that stimulate epithelial cells may lead to new insights into controlling lung inflammation. This study sought to investigate the responsiveness of human lung epithelial cells to the TNF family molecules LIGHT and lymphotoxin αβ (LTαβ). Bronchial and alveolar epithelial cell lines, and primary human bronchial epithelial cells, were stimulated with LIGHT and LTαβ, and expression of inflammatory cytokines and chemokines, and markers of epithelial-mesenchymal transition and fibrosis/remodeling, were measured. LTβR, the receptor shared by LIGHT and LTαβ, was constitutively expressed on all epithelial cells. Correspondingly, LIGHT and LTαβ strongly induced a limited but highly distinct set of inflammatory genes in all epithelial cells tested, namely the adhesion molecules ICAM-1 and VCAM-1; the chemokines CCL5, CCL20, CXCL1, CXCL3, CXCL5 and CXCL11; the cytokines IL-6, activin A, and GM-CSF; and metalloproteinases MMP-9 and ADAM-8. Importantly, induction of the majority of these inflammatory molecules was insensitive to the suppressive effects of the corticosteroid budesonide. LIGHT and LTαβ also moderately downregulated E-cadherin, a protein associated with maintaining epithelial integrity, but did not significantly drive production of extracellular matrix proteins or alpha-smooth muscle actin. Thus, LIGHT and LTαβ induce a distinct steroid-resistant inflammatory signature in airway epithelial cells via constitutively expressed LTβR. These findings support our prior murine studies that suggested the receptors for LIGHT and LTαβ contribute to development of lung inflammation characteristic of asthma and idiopathic pulmonary fibrosis.