Division of Immune Regulation, La Jolla Institute for Allergy and Immunology, La Jolla, CA, United States.
Janssen Research and Development, LLC, Immunology Discovery Research, Spring House, PA, United States.
Front Immunol. 2018 Mar 19;9:576. doi: 10.3389/fimmu.2018.00576. eCollection 2018.
The cytokine TNFSF14 [homologous to Lymphotoxin, exhibits Inducible expression and competes with HSV Glycoprotein D for binding to HVEM, a receptor expressed on T lymphocytes (LIGHT)] has been shown in mouse models to be important for development of lung tissue remodeling that is characteristic of asthma, idiopathic pulmonary fibrosis (IPF), and systemic sclerosis (SSc). However, its cellular targets are not fully delineated. In the present report, we show that LTβR and HVEM, the receptors for LIGHT, are constitutively expressed in primary human lung fibroblasts (HLFs). We asked whether LIGHT could promote inflammatory and remodeling-relevant activity in HLFs and how this was similar to, or distinct from, IL-13 or TGF-β, two cytokines strongly implicated in the pathogenesis of asthma, IPF, and SSc. Accumulation of myofibroblasts expressing alpha smooth muscle actin is a feature of lung inflammatory diseases. LIGHT promoted cell cycle progression and proliferation of HLFs, but not alpha smooth muscle actin expression. In contrast, TGF-β upregulated alpha smooth muscle actin but did not drive their proliferation. LIGHT also increased the gene or protein expression of a number of proinflammatory mediators, including ICAM-1 and VCAM-1, IL-6 and GM-CSF, the chemokines CCL5 and 20, and CXCL5, 11, and 12, and lung remodeling-associated proteinases MMP-9 and ADAM8. These were dependent on LTβR but not HVEM. LIGHT displayed overlapping and synergistic activities with IL-13 for a number of the activities, but LIGHT additionally enhanced the gene expression of several molecules, including the innate cytokines IL-33 and TSLP, which were not upregulated by IL-13. Our results highlight the varied and pleiotropic effects of LIGHT in HLFs. LIGHT might then be a therapeutic target for modulation of inflammation and remodeling associated with asthma and other similar diseases of the lung that involve fibroblasts.
细胞因子 TNFSF14（与淋巴毒素同源，表现出诱导表达，并与 HVEM 竞争结合，HVEM 是 T 淋巴细胞上表达的受体[LIGHT]）已在小鼠模型中表明对于哮喘、特发性肺纤维化（IPF）和系统性硬化症（SSc）特征性的肺组织重塑的发展很重要。然而，其细胞靶标尚未完全确定。在本报告中，我们表明，LIGHT 的受体 LTβR 和 HVEM 在原代人肺成纤维细胞（HLFs）中持续表达。我们询问 LIGHT 是否可以促进 HLFs 中的炎症和重塑相关活性，以及它与 IL-13 或 TGF-β（两种强烈参与哮喘、IPF 和 SSc 发病机制的细胞因子）有何相似或不同之处。表达α平滑肌肌动蛋白的肌成纤维细胞的积累是肺部炎症性疾病的特征。LIGHT 促进了 HLFs 的细胞周期进展和增殖，但不促进α平滑肌肌动蛋白的表达。相比之下，TGF-β上调了α平滑肌肌动蛋白，但没有驱动其增殖。LIGHT 还增加了许多促炎介质的基因或蛋白表达，包括 ICAM-1 和 VCAM-1、IL-6 和 GM-CSF、趋化因子 CCL5 和 20 以及 CXCL5、11 和 12，以及与肺重塑相关的蛋白酶 MMP-9 和 ADAM8。这些依赖于 LTβR 而不是 HVEM。对于许多活性，LIGHT 与 IL-13 显示出重叠和协同作用，但 LIGHT 还另外增强了一些分子的基因表达，包括先天细胞因子 IL-33 和 TSLP，这些分子不受 IL-13 的上调。我们的结果突出了 LIGHT 在 HLFs 中的多种和多效作用。然后，LIGHT 可能成为治疗哮喘和其他涉及成纤维细胞的类似肺部疾病的炎症和重塑的靶点。
