Laboratory of Molecular Immunology and Embryology, University of Orléans, Orléans, France.
Am J Respir Cell Mol Biol. 2011 Oct;45(4):731-9. doi: 10.1165/rcmb.2010-0512OC. Epub 2011 Feb 4.
Tumor Necrosis Factor (TNF) is a pleiotropic cytokine consisting of soluble and transmembrane forms, with distinct roles in inflammation and immunity. TNF is an important factor in allergic airway inflammation. However, the disparate functions of soluble (sol) and transmembrane (tm) TNF in lung pathology are not well understood. Our aim was to assess the activities of solTNF and tmTNF in murine models of allergic airway disease, and to evaluate the efficacy of solTNF-selective inhibition. We used ovalbumin sensitization and challenge of TNF knockout, tmTNF knockin, and wild-type C57BL/6 mice to distinguish differences in airway inflammation and hyperreactivity mediated by solTNF and tmTNF. Functions of solTNF and tmTNF in hyperresponsive, wild-type Balb/c mice were assessed by comparing dominant-negative anti-TNF biologics, which antagonize solTNF yet spare tmTNF, to etanercept, a nonselective inhibitor of both TNF forms. Responses in transgenic C57BL/6 mice demonstrated that solTNF, and not tmTNF, is necessary to drive airway inflammation. In Balb/c mice, dominant-negative TNF biologics administered during immunization decreased the recruitment of eosinophils and lymphocytes into the bronchoalveolar space and lung parenchyma, reduced specific serum IgE, goblet-cell hyperplasia, and eosinophilic inflammation, and suppressed methacholine-induced airway hyperreactivity. Concentrations of IL-5, CCL5/RANTES, CCL11/eotaxin, and CCL17/TARC were also reduced in bronchoalveolar lavage. Dominant-negative TNFs reduced lung eosinophilia, even when given only during antigen challenge. The selective inhibition of soluble TNF suppresses inflammation, hyperreactivity, and remodeling in transgenic and wild-type murine models of allergic airway disease, and may offer safety advantages in therapies that preserve the immunoprotective functions of transmembrane TNF.
肿瘤坏死因子（TNF）是一种具有多种生物学活性的细胞因子，由 157 个氨基酸组成，相对分子质量为 26KD，它是一种重要的炎症反应和免疫调节因子，在过敏性哮喘气道炎症中起重要作用。然而，可溶性（sol）和跨膜（tm）TNF 在肺部病理中的不同功能尚不清楚。本研究旨在评估可溶性 TNF 和跨膜 TNF 在过敏性气道疾病小鼠模型中的活性，并评估可溶性 TNF 选择性抑制的疗效。我们使用卵清蛋白致敏和挑战 TNF 敲除、tmTNF 敲入和野生型 C57BL/6 小鼠，以区分 solTNF 和 tmTNF 介导的气道炎症和高反应性的差异。通过比较拮抗 solTNF 而不拮抗 tmTNF 的显性负性抗 TNF 生物制剂与非选择性抑制两种 TNF 形式的依那西普，评估 solTNF 和 tmTNF 在高反应性野生型 Balb/c 小鼠中的功能。转基因 C57BL/6 小鼠的反应表明，是 solTNF 而不是 tmTNF 驱动气道炎症。在 Balb/c 小鼠中，免疫接种期间给予的显性负性 TNF 生物制剂可减少嗜酸性粒细胞和淋巴细胞向支气管肺泡腔和肺实质的募集，减少特异性血清 IgE、杯状细胞增生和嗜酸性粒细胞炎症，并抑制乙酰甲胆碱诱导的气道高反应性。支气管肺泡灌洗液中 IL-5、CCL5/RANTES、CCL11/eotaxin 和 CCL17/TARC 的浓度也降低。即使仅在抗原挑战期间给予显性负性 TNF，也可减少肺嗜酸性粒细胞。可溶性 TNF 的选择性抑制可抑制转基因和野生型过敏性气道疾病小鼠模型中的炎症、高反应性和重塑，并且在保留跨膜 TNF 的免疫保护功能的治疗中可能具有安全性优势。
