Kang Min-Jong, Homer Robert J, Gallo Amy, Lee Chun Geun, Crothers Kristina A, Cho Soo Jung, Rochester Carolyn, Cain Hilary, Chupp Geoffrey, Yoon Ho Joo, Elias Jack A
Section of Pulmonary and Critical Care Medicine, Yale University School of Medicine, New Haven, CT 06520, USA.
J Immunol. 2007 Feb 1;178(3):1948-59. doi: 10.4049/jimmunol.178.3.1948.
Th1 inflammation and remodeling characterized by local tissue destruction coexist in pulmonary emphysema and other diseases. To test the hypothesis that IL-18 plays an important role in these responses, we characterized the regulation of IL-18 in lungs from cigarette smoke (CS) and room air-exposed mice and characterized the effects of CS in wild-type mice and mice with null mutations of IL-18Ralpha (IL-18Ralpha(-/-)). CS was a potent stimulator and activator of IL-18 and caspases 1 and 11. In addition, although CS caused inflammation and emphysema in wild-type mice, both of these responses were significantly decreased in IL-18Ralpha(-/-) animals. CS also induced epithelial apoptosis, activated effector caspases and stimulated proteases and chemokines via IL-18Ralpha-dependent pathways. Importantly, the levels of IL-18 and its targets, cathepsins S and B, were increased in pulmonary macrophages from smokers and patients with chronic obstructive lung disease. Elevated levels of circulating IL-18 were also seen in patients with chronic obstructive lung disease. These studies demonstrate that IL-18 and the IL-18 pathway are activated in CS-exposed mice and man. They also demonstrate, in a murine modeling system, that IL-18R signaling plays a critical role in the pathogenesis of CS-induced inflammation and emphysema.
以局部组织破坏为特征的Th1炎症和重塑在肺气肿及其他疾病中共存。为了验证白细胞介素18（IL-18）在这些反应中起重要作用的假说，我们对暴露于香烟烟雾（CS）和室内空气的小鼠肺中IL-18的调节进行了表征，并对CS在野生型小鼠和IL-18Rα基因敲除（IL-18Rα(-/-)）小鼠中的作用进行了表征。CS是IL-18、半胱天冬酶1和11的强效刺激物和激活剂。此外，虽然CS在野生型小鼠中引起炎症和肺气肿，但在IL-18Rα(-/-)动物中这两种反应均显著降低。CS还通过IL-18Rα依赖途径诱导上皮细胞凋亡、激活效应半胱天冬酶并刺激蛋白酶和趋化因子。重要的是，吸烟者和慢性阻塞性肺疾病患者肺巨噬细胞中IL-18及其靶标组织蛋白酶S和B的水平升高。慢性阻塞性肺疾病患者循环中IL-18水平也升高。这些研究表明，在暴露于CS的小鼠和人类中，IL-18和IL-18途径被激活。它们还在小鼠模型系统中表明，IL-18R信号传导在CS诱导的炎症和肺气肿发病机制中起关键作用。
