Activation of peroxisome proliferator-activated receptor-γ in dendritic cells inhibits the development of eosinophilic airway inflammation in a mouse model of asthma
Activation of peroxisome proliferator-activated receptor-γ in dendritic cells inhibits the development of eosinophilic airway inflammation in a mouse model of asthma
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DOI：
10.1016/s0002-9440(10)63116-1
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发表时间：
2004-01-01
影响因子：
6
通讯作者：
Lambrecht, BN
中科院分区：
文献类型：
--
作者：
Hammad, H;de Heer, HJ;Lambrecht, BN
过氧化物酶体增殖物激活受体（PPARs）被一系列多不饱和脂肪酸衍生物、氧化脂肪酸和磷脂激活，被认为是免疫和炎症反应的重要调节剂。最近，我们发现，激活的PPAR-gamma改变了树突状细胞（DC），最有效的抗原呈递细胞的成熟过程。在本报告中，我们研究了通过靶向DC，PPAR-gamma激活可能参与调节对变应原的肺免疫应答的可能性。使用致敏模型，基于卵清蛋白（OVA）脉冲的DC的气管内转移，我们表明，罗格列酮，一种选择性的PPAR-gamma激动剂，减少了引流纵隔淋巴结中Ag-特异性T细胞的增殖，但令人惊讶的是，与用OVA脉冲的DC致敏的对照小鼠相比，显著增加了T细胞产生的免疫调节细胞因子白细胞介素（ILL）-10。气雾剂激发后，与对照小鼠相比，支气管肺泡灌洗液中嗜酸性粒细胞的募集显著减少。最后，来自纵隔淋巴结的T细胞产生更高量的IL-10和干扰素-γ。用抗IL-10 R抗体抑制IL-10活性部分恢复了炎症。通过用另一种PPAR-gamma激动剂ciglitazone和PPAR-gamma拮抗剂GW 9662处理OVA脉冲的DC证实了这种现象的特异性。我们的数据表明，PPAR-gamma激活防止诱导Th 2依赖性嗜酸性气道炎症，并可能有助于肺免疫稳态。
Peroxisome proliferator-activated receptors (PPARs) are activated by an array of polyunsaturated fatty acid derivatives, oxidized fatty acids, and phospholipids and are proposed to be important modulators of immune and inflammatory responses. Recently, we showed that activation of PPAR-gamma alters the maturation process of dendritic cells (DCs), the most potent antigen-presenting cells. in the present report, we investigated the possibility that, by targeting DCs, PPAR-gamma activation may be involved in the regulation of the pulmonary immune response to allergens. Using a model of sensitization, based on the intratracheal transfer of ovalbumin (OVA)-pulsed DCs, we show that rosiglitazone, a selective PPAR-gamma agonist, reduces the proliferation of Ag-speciric T cells in the draining mediastinal lymph nodes but, surprisingly enough, dramatically increases the production of the immunoregulatory cytokine interleukin (ILL)-10 by T cells, as compared to control mice sensitized with OVA-pulsed DCs. After aerosol challenge, the recruitment of eosinophils; in the bronchoalveolar lavage fluids was strongly reduced compared to control mice. Finally, T cells from the mediastinal lymph nodes produced higher amounts of IL-10 and interferon-gamma. Inhibition of IL-10 activity with anti-IL-10R antibodies partly restored the inflammation. The specificity of the phenomenon was confirmed by treating OVA-pulsed DCs with ciglitazone, another PPAR-gamma agonist, and by using GW9662, a PPAR-gamma antagonist. Our data suggest that PPAR-gamma activation prevents induction of Th2-dependent eosinophilic airway inflammation and might contribute to immune homeostasis in the lung.