Chakrabarty Kaushik, Wu Wenxin, Booth J Leland, Duggan Elizabeth S, Nagle Nancy N, Coggeshall K Mark, Metcalf Jordan P
University of Oklahoma Health Sciences Center, 800 N. Research Parkway, Oklahoma City, OK 73104, USA.
Infect Immun. 2007 Aug;75(8):3729-38. doi: 10.1128/IAI.00046-07. Epub 2007 May 21.
Bacillus anthracis, the causative agent of inhalational anthrax, enters a host through the pulmonary system before dissemination. We have previously shown that human alveolar macrophages participate in the initial innate immune response to B. anthracis spores through cell signal-mediated cytokine release. We proposed that the lung epithelia also participate in the innate immune response to this pathogen, and we have developed a human lung slice model to study this process. Exposure of our model to B. anthracis (Sterne) spores rapidly activated the mitogen-activated protein kinase signaling pathways ERK, p38, and JNK. In addition, an RNase protection assay showed induction of mRNA of several cytokines and chemokines. This finding was reflected at the translational level by protein peak increases of 3-, 25-, 9-, 34-, and 5-fold for interleukin-6 (IL-6), tumor necrosis factor alpha, IL-8, macrophage inflammatory protein 1alpha/beta, and monocyte chemoattractant protein 1, respectively, as determined by an enzyme-linked immunosorbent assay. Inhibition of individual pathways by UO126, SP600125, and SB0203580 decreased induction of chemokines and cytokines by spores, but this depended on the pathways inhibited and the cytokines and chemokines induced. Combining all three inhibitors reduced induction of all cytokines and chemokines tested to background levels. An immunohistochemistry analysis of IL-6 and IL-8 revealed that alveolar epithelial cells and macrophages and a few interstitial cells are the source of the cytokines and chemokines. Taken together, these data showed the activation of the pulmonary epithelium in response to B. anthracis spore exposure. Thus, the lung epithelia actively participate in the innate immune response to B. anthracis infection through cell signal-mediated elaboration of cytokines and chemokines.
吸入性炭疽的病原体炭疽芽孢杆菌在扩散之前通过肺部系统进入宿主。我们之前已经表明，人类肺泡巨噬细胞通过细胞信号介导的细胞因子释放参与对炭疽芽孢杆菌孢子的初始固有免疫反应。我们提出肺上皮细胞也参与对这种病原体的固有免疫反应，并且我们已经建立了一个人类肺切片模型来研究这个过程。将我们的模型暴露于炭疽芽孢杆菌（Sterne）孢子中会迅速激活丝裂原活化蛋白激酶信号通路ERK、p38和JNK。此外，核糖核酸酶保护试验显示几种细胞因子和趋化因子的mRNA被诱导。通过酶联免疫吸附测定法确定，这一发现反映在翻译水平上，白细胞介素-6（IL-6）、肿瘤坏死因子α、IL-8、巨噬细胞炎性蛋白1α/β和单核细胞趋化蛋白1的蛋白质峰值分别增加了3倍、25倍、9倍、34倍和5倍。用UO126、SP600125和SB0203580抑制单个通路会降低孢子诱导的趋化因子和细胞因子，但这取决于所抑制的通路以及所诱导的细胞因子和趋化因子。联合使用所有三种抑制剂可将所有测试的细胞因子和趋化因子的诱导降低至背景水平。对IL-6和IL-8的免疫组织化学分析表明，肺泡上皮细胞、巨噬细胞和一些间质细胞是细胞因子和趋化因子的来源。综上所述，这些数据表明肺上皮细胞在暴露于炭疽芽孢杆菌孢子时被激活。因此，肺上皮细胞通过细胞信号介导的细胞因子和趋化因子的分泌，积极参与对炭疽芽孢杆菌感染的固有免疫反应。
