Role of CCR5 in IFN-γ-induced and cigarette smoke-induced emphysema
Role of CCR5 in IFN-γ-induced and cigarette smoke-induced emphysema
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DOI：
10.1172/jci24858
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发表时间：
2005-12-01
影响因子：
15.9
通讯作者：
Elias, JA
中科院分区：
文献类型：
--
作者：
Ma, B;Kang, MJ;Elias, JA
Th 1炎症和以组织破坏为特征的重塑在人类疾病中经常共存。为了进一步理解这些反应的机制，我们确定了CCR 5在小鼠肺气肿模型中IFN-γ诱导的炎症和重塑的发病机制中的作用。IFN-γ是CCRS配体巨噬细胞炎性蛋白-1 α/CCL-3（MIP-1 α/CCL-3）、MIP-1 β/CCL-4和RANTES/CCL-5等的有效刺激物。CCR 5的抗体中和或无效突变减少IFN-γ诱导的炎症、DNA损伤、细胞凋亡和肺泡重塑。这些干预措施降低了选择趋化因子的表达，包括CCR 5配体和MMP-9，并增加了分泌性白细胞蛋白酶抑制剂的水平。它们还降低Fas、FasL、TNF、caspase-3、-8和-9、Bid和Bax的表达和/或活化。根据这些发现，香烟烟雾通过IFN-γ依赖性途径诱导肺部炎症、DNA损伤、细胞凋亡和肺气肿，CCRS的无效突变降低了这些反应。这些研究表明，IFN-γ是CC和CXC趋化因子的有效刺激物，并强调了CCR 5在IFN-γ诱导的和香烟烟雾诱导的炎症、组织重塑和肺气肿的发病机制中的重要性。他们还证明，CCR 5是其自身配体、其他趋化因子、MMP、半胱天冬酶和细胞死亡调节因子的最佳IFN-γ刺激以及抗蛋白酶抑制所必需的。
Th1 inflammation and remodeling characterized by tissue destruction frequently coexist in human diseases. To further understand the mechanisms of these responses, we defined the role(s) of CCR5 in the pathogenesis of IFN-gamma-induced inflammation and remodeling in a murine emphysema model. IFN-gamma was a potent stimulator of the CCRS ligands macrophage inflammatory protein-1 alpha/CCL-3 (MIP-1 alpha/CCL-3), MIP-1 beta/CCL-4, and RANTES/CCL-5, among others. Antibody neutralization or null mutation of CCR5 decreased IFN-gamma-induced inflammation, DNA injury, apoptosis, and alveolar remodeling. These interventions decreased the expression of select chemokines, including CCR5 ligands and MMP-9, and increased levels of secretory leukocyte protease inhibitor. They also decreased the expression and/or activation of Fas, FasL, TNF, caspase-3,-8, and -9, Bid, and Bax. In accordance with these findings, cigarette smoke induced pulmonary inflammation, DNA injury, apoptosis, and emphysema via an IFN-gamma-dependent pathway(s), and a null mutation of CCRS decreased these responses. These studies demonstrate that IFN-gamma is a potent stimulator of CC and CXC chemokines and highlight the importance of CCR5 in the pathogenesis of IFN-gamma-induced and cigarette smoke-induced inflammation, tissue remodeling, and emphysema. They also demonstrate that CCR5 is required for optimal IFN-gamma stimulation of its own ligands, other chemokines, MMPs, caspases, and cell death regulators and the inhibition of antiproteases.