Wang J, Palmer K, Lŏtvall J, Milan S, Lei X F, Matthaei K I, Gauldie J, Inman M D, Jordana M, Xing Z
Immunology and Infection Program, Department of Pathology and Molecular Medicine, McMaster University, Hamilton, Ontario, Canada L8N 3Z5.
J Clin Invest. 1998 Sep 15;102(6):1132-41. doi: 10.1172/JCI2686.
IL-5 is induced locally in the lung and systemically in the circulation during allergic airways eosinophilic inflammation both in humans and experimental animals. However, the precise role of local and systemic IL-5 in the development of allergic airways eosinophilia remains to be elucidated. In our current study, we demonstrate that compared with their IL-5(+/+) counterparts, IL-5(-/-) mice lacked an IL-5 response both in the lung and peripheral blood, yet they released similar amounts of IL-4, eotaxin, and MIP-1alpha in the lung after ovalbumin (OVA) sensitization and challenge. At cellular levels, these mice failed to develop peripheral blood and airways eosinophilia while the responses of lymphocytes, neutrophils, and macrophages remained similar to those in IL-5(+/+) mice. To dissect the relative role of local and systemic IL-5 in this model, we constructed a gene transfer vector expressing murine IL-5. Intramuscular IL-5 gene transfer to OVA-sensitized IL-5(-/-) mice led to raised levels of IL-5 compartmentalized to the circulation and completely reconstituted airways eosinophilia upon OVA challenge, which was associated with reconstitution of eosinophilia in the bone marrow and peripheral blood. Significant airways eosinophilia was observed for at least 7 d in these mice. In contrast, intranasal IL-5 gene transfer, when rendered to give rise to a significant but compartmentalized level of transgene protein IL-5 in the lung, was unable to reconstitute airways eosinophilia in OVA-sensitized IL-5(-/-) mice upon OVA-challenge, which was associated with a lack of eosinophilic responses in bone marrow and peripheral blood. Our findings thus provide unequivocal evidence that circulating but not local lung IL-5 is critically required for the development of allergic airways eosinophilia. These findings also provide the rationale for developing strategies to target circulating IL-5 and/or its receptors in bone marrow to effectively control asthmatic airways eosinophilia.
在人类和实验动物的过敏性气道嗜酸性粒细胞炎症过程中，白细胞介素-5（IL-5）在肺部局部诱导产生，并在循环系统中全身性诱导产生。然而，局部和全身性IL-5在过敏性气道嗜酸性粒细胞增多症发展中的精确作用仍有待阐明。在我们目前的研究中，我们证明，与IL-5(+/+) 同窝小鼠相比，IL-5(-/-) 小鼠在肺部和外周血中均缺乏IL-5反应，但在卵清蛋白（OVA）致敏和激发后，它们在肺部释放的IL-4、嗜酸性粒细胞趋化因子和巨噬细胞炎性蛋白-1α 量相似。在细胞水平上，这些小鼠未能出现外周血和气道嗜酸性粒细胞增多，而淋巴细胞、中性粒细胞和巨噬细胞的反应仍与IL-5(+/+) 小鼠相似。为了剖析局部和全身性IL-5在该模型中的相对作用，我们构建了一个表达小鼠IL-5的基因转移载体。对OVA致敏的IL-5(-/-) 小鼠进行肌肉内IL-5基因转移，导致循环系统中IL-5水平升高，并在OVA激发后完全重建气道嗜酸性粒细胞增多，这与骨髓和外周血中嗜酸性粒细胞增多的重建有关。在这些小鼠中观察到显著的气道嗜酸性粒细胞增多至少持续7天。相比之下，鼻内IL-5基因转移在肺部产生显著但局部化的转基因蛋白IL-5水平时，在OVA激发后无法在OVA致敏的IL-5(-/-) 小鼠中重建气道嗜酸性粒细胞增多，这与骨髓和外周血中缺乏嗜酸性粒细胞反应有关。因此，我们的研究结果提供了明确的证据，即循环中的而非局部肺部的IL-5是过敏性气道嗜酸性粒细胞增多症发展所必需的。这些研究结果还为制定针对循环中的IL-5及其在骨髓中的受体的策略提供了理论依据，以有效控制哮喘气道嗜酸性粒细胞增多。
