Department of Biomedical Sciences, College of Medicine, Hanyang University, Seoul, Korea.
Clin Exp Allergy. 2011 Aug;41(8):1143-56. doi: 10.1111/j.1365-2222.2011.03792.x. Epub 2011 Jun 14.
Asthma is an inflammatory disease of the airways that is mediated by Th2 responses. Poly-γ-glutamic acid (γ-PGA) is an extracellular polymeric compound that is synthesized by Bacillus cells. Previously, we found that γ-PGA promoted Th1 cell development in a manner dependent on antigen-presenting cells, but inhibited Th2 cell development.
To investigate the effect of γ-PGA on dendritic cells (DCs), and its potential for treating Th2-mediated allergic asthma.
Wild-type, Toll-like receptor (TLR)-2 deficient, and TLR-4-defective mice were used. DCs derived from the bone marrow and extracted from the lung were stimulated with γ-PGA and assayed for the expression of signalling molecules, costimulatory molecules, and cytokines. Mice were sensitized and challenged with ovalbumin (OVA) to induce asthma. They were repeatedly injected intranasally with γ-PGA before and during the challenge period, and inflammation and structural remodelling of the airways were examined.
γ-PGA selectively signalled conventional DCs to activate NF-κB and mitogen-activated protein kinase, leading to the up-regulation of CD86, CD40, and IL-12, but not IL-10 and IL-6. These effects of γ-PGA were dependent on TLR-4 and independent of TLR-2. Importantly, the intranasal administration of γ-PGA to OVA-sensitized/challenged mice reduced the airway hyperresponsiveness and allergic inflammation such as leucocyte influx, goblet cell hyperplasia, eosinophilia, and Th2 cytokine production. In addition to lowered IgE titres, the treatment of mice with γ-PGA significantly reduced the multiplication and Th2 polarization of mediastinal lymph node T cells upon allergen-specific restimulation. These anti-asthmatic effects of γ-PGA were also abolished in TLR-4-defective mice.
Our data indicate that γ-PGA activates DCs to favour Th1 cell induction through a TLR-4-dependent pathway and alleviates pathologic symptoms in a Th2-biased asthmatic model. These findings highlight the potential of γ-PGA for the treatment of asthma and other allergic disease in which Th2 polarization plays an important role.
哮喘是一种气道炎症性疾病，由 Th2 反应介导。聚γ-谷氨酸（γ-PGA）是一种由芽孢杆菌细胞合成的细胞外多聚物。先前，我们发现 γ-PGA 通过抗原呈递细胞促进 Th1 细胞的发育，但抑制 Th2 细胞的发育。
研究 γ-PGA 对树突状细胞（DC）的影响及其在治疗 Th2 介导的过敏性哮喘中的潜力。
使用野生型、Toll 样受体（TLR）-2 缺陷型和 TLR-4 缺陷型小鼠。从骨髓中提取并从肺部提取的 DC 用 γ-PGA 刺激，并检测信号分子、共刺激分子和细胞因子的表达。用卵清蛋白（OVA）致敏和攻击小鼠，诱导哮喘。在攻击期间，反复给予 γ-PGA 鼻内注射，并检查气道的炎症和结构重塑。
γ-PGA 选择性地对传统 DC 发出信号，激活 NF-κB 和丝裂原活化蛋白激酶，导致 CD86、CD40 和 IL-12 的上调，但不导致 IL-10 和 IL-6 的上调。γ-PGA 的这些作用依赖于 TLR-4，而不依赖于 TLR-2。重要的是，给 OVA 致敏/攻击的小鼠鼻内给予 γ-PGA 可降低气道高反应性和过敏性炎症，如白细胞浸润、杯状细胞增生、嗜酸性粒细胞增多和 Th2 细胞因子产生。除了降低 IgE 滴度外，γ-PGA 治疗还可显著减少过敏原特异性再刺激时纵隔淋巴结 T 细胞的增殖和 Th2 极化。在 TLR-4 缺陷型小鼠中，γ-PGA 的这些抗哮喘作用也被消除。
我们的数据表明，γ-PGA 通过 TLR-4 依赖性途径激活 DC，有利于 Th1 细胞的诱导，并缓解 Th2 偏倚哮喘模型中的病理症状。这些发现强调了 γ-PGA 在治疗哮喘和其他 Th2 极化起重要作用的过敏性疾病中的潜力。
