Warfel Jason M, D'Agnillo Felice
Laboratory of Biochemistry and Vascular Biology, Division of Hematology, Center for Biologics Evaluation and Research, Food and Drug Administration, Bethesda, MD 20892.
J Immunol. 2008 Jun 1;180(11):7516-24. doi: 10.4049/jimmunol.180.11.7516.
Impaired host defenses and vascular dysfunction are hallmarks of the late, antibiotic-refractory stages of systemic anthrax infection. Anthrax lethal toxin (LT), a key virulence factor of Bacillus anthracis, was previously shown to enhance VCAM-1 expression on primary human endothelial cells suggesting a causative link between dysregulated adhesion molecule expression and the poor immune response and vasculitis associated with anthrax. In this study, we report that LT amplification of TNF-induced VCAM-1 expression is driven transcriptionally by the cooperative activation of NF-kappaB and IFN regulatory factor-1 (IRF-1). LT enhancement of NF-kappaB phosphorylation and nuclear translocation correlated temporally with a delayed reaccumulation of IkappaBalpha, while increased induction of IRF-1 was linked to STAT1 activation. LT failed to augment TNF-induced ICAM-1 or E-selectin expression, two adhesion molecules regulated by NF-kappaB, but not IRF-1. These results suggest that LT can differentially modulate NF-kappaB target genes and highlight the importance of IRF-1 in VCAM-1 enhancement. Altering the activity of key transcription factors involved in host response to infection may be a critical mechanism by which LT contributes to anthrax pathogenesis.
宿主防御功能受损和血管功能障碍是系统性炭疽感染晚期抗生素难治阶段的特征。炭疽致死毒素（LT）是炭疽芽孢杆菌的关键毒力因子，先前已证明它能增强原代人内皮细胞上血管细胞黏附分子-1（VCAM-1）的表达，提示黏附分子表达失调与炭疽相关的免疫反应不佳和血管炎之间存在因果关系。在本研究中，我们报告LT对肿瘤坏死因子（TNF）诱导的VCAM-1表达的放大作用是由核因子κB（NF-κB）和干扰素调节因子-1（IRF-1）的协同激活转录驱动的。LT增强NF-κB磷酸化和核转位与IκBα延迟重新积累在时间上相关，而IRF-1诱导增加与信号转导和转录激活因子1（STAT1）激活有关。LT未能增强TNF诱导的细胞间黏附分子-1（ICAM-1）或E-选择素表达，这两种黏附分子由NF-κB调节，但不由IRF-1调节。这些结果表明，LT可以差异调节NF-κB靶基因，并突出了IRF-1在增强VCAM-1表达中的重要性。改变参与宿主对感染反应的关键转录因子的活性可能是LT促成炭疽发病机制的关键机制。
