Han Wei, Joo Myungsoo, Everhart M Brett, Christman John W, Yull Fiona E, Blackwell Timothy S
Department of Medicine, Division of Allergy, Pulmonary, Vanderbilt University School of Medicine, Nashville, Tennessee USA.
Am J Physiol Lung Cell Mol Physiol. 2009 Mar;296(3):L320-7. doi: 10.1152/ajplung.90485.2008. Epub 2008 Dec 19.
Although acute lung inflammation in response to local or systemic infection involves myeloid and nonmyeloid cells, the interplay between different cell types remains poorly defined. Since NF-kappaB is a key transcription factor for innate immunity, we investigated whether dysregulated NF-kappaB activation in myeloid cells impacts inflammatory signaling in nonmyeloid cells and generation of neutrophilic lung inflammation in response to systemic endotoxemia. We generated bone marrow chimeras by fetal liver transplantation of cells deficient in IkappaBalpha or p50 into lethally irradiated NF-kappaB reporter transgenic mice. No differences were apparent between bone marrow chimeras in the absence of an inflammatory stimulus; however, following intraperitoneal injection of Escherichia coli lipopolysaccharide (LPS), IkappaBalpha- or p50-deficient bone marrow chimeras showed increased NF-kappaB activation in nonhematopoietic cells, exaggerated neutrophilic inflammation, and higher mortality compared with untransplanted reporter mice and wild-type bone marrow chimeras. Primary bone marrow-derived macrophages (BMDM) from IkappaBalpha(-/-) or p50(-/-) exhibited increased NF-kappaB activation and macrophage inflammatory protein-2 production after LPS treatment compared with wild-type cells, and coculture of BMDM with lung epithelial (A549) cells resulted in increased NF-kappaB activation in A549 cells and excess IL-8 production by these epithelial cells. These studies indicate an important role for inhibitory members of the NF-kappaB family acting specifically within myeloid cells to limit inflammatory responses in the lungs.
尽管针对局部或全身感染的急性肺部炎症涉及髓样细胞和非髓样细胞，但不同细胞类型之间的相互作用仍不清楚。由于核因子κB（NF-κB）是先天免疫的关键转录因子，我们研究了髓样细胞中NF-κB激活失调是否会影响非髓样细胞中的炎症信号传导以及对全身内毒素血症的嗜中性粒细胞性肺部炎症的产生。我们通过将缺乏IkappaBalpha或p50的细胞进行胎肝移植到经致死剂量照射的NF-κB报告基因转基因小鼠中，构建了骨髓嵌合体。在没有炎症刺激的情况下，骨髓嵌合体之间没有明显差异；然而，腹腔注射大肠杆菌脂多糖（LPS）后，与未移植的报告基因小鼠和野生型骨髓嵌合体相比，缺乏IkappaBalpha或p50的骨髓嵌合体在非造血细胞中显示出增加的NF-κB激活、过度的嗜中性粒细胞炎症和更高的死亡率。与野生型细胞相比，来自IkappaBalpha（-/-）或p50（-/-）的原代骨髓来源巨噬细胞（BMDM）在LPS处理后表现出增加的NF-κB激活和巨噬细胞炎性蛋白-2产生，并且BMDM与肺上皮（A549）细胞共培养导致A549细胞中NF-κB激活增加以及这些上皮细胞产生过量的白细胞介素-8。这些研究表明NF-κB家族的抑制成员在髓样细胞中特异性发挥作用以限制肺部炎症反应具有重要作用。
