Xu Lixin, Fang Hui, Frucht David M
Division of Monoclonal Antibodies, Office of Biotechnology Products, Office of Pharmaceutical Science, Center for Drug Evaluation and Research, US Food and Drug Administration, Bethesda, MD 20892, USA.
J Immunol. 2008 Mar 15;180(6):4139-47. doi: 10.4049/jimmunol.180.6.4139.
The combination of lethal factor and its receptor-binding partner, protective Ag, is termed lethal toxin (LT) and has critical pathogenic activity during infection with Bacillus anthracis. We herein report that anthrax LT binds and enters murine neutrophils, leading to the cleavage of mitogen-activated protein kinase kinase/MEK/MAPKK 1-4 and 6, but not mitogen-activated protein kinase kinase 5 and 7. Anthrax LT treatment of neutrophils disrupts signaling to downstream MAPK targets in response to TLR stimulation. Following anthrax LT treatment, ERK family and p38 phosphorylation are nearly completely blocked, but signaling to JNK family members persists in vitro and ex vivo. In contrast to previous reports involving human neutrophils, anthrax LT treatment of murine neutrophils increases their production of superoxide in response to PMA or TLR stimulation in vitro or ex vivo. Although this enhanced superoxide production correlates with effects due to the LT-induced blockade of ERK signaling, it requires JNK signaling that remains largely intact despite the activity of anthrax LT. These findings reveal a previously unrecognized mechanism through which anthrax LT supports a critical proinflammatory response of murine neutrophils.
致死因子与其受体结合伴侣保护性抗原的组合被称为致死毒素（LT），在炭疽芽孢杆菌感染期间具有关键的致病活性。我们在此报告，炭疽毒素LT能结合并进入小鼠中性粒细胞，导致丝裂原活化蛋白激酶激酶/MEK/MAPKK 1 - 4和6的裂解，但不会导致丝裂原活化蛋白激酶激酶5和7的裂解。用炭疽毒素LT处理中性粒细胞会破坏响应TLR刺激向下游MAPK靶点的信号传导。用炭疽毒素LT处理后，ERK家族和p38磷酸化几乎完全被阻断，但在体外和体内，向JNK家族成员的信号传导仍然存在。与之前涉及人类中性粒细胞的报道不同，用炭疽毒素LT处理小鼠中性粒细胞会增加其在体外或体内对PMA或TLR刺激产生超氧化物的能力。尽管这种超氧化物产生的增强与LT诱导的ERK信号传导阻断的效应相关，但它需要JNK信号传导，尽管炭疽毒素LT有活性，JNK信号传导在很大程度上仍保持完整。这些发现揭示了一种以前未被认识的机制，通过该机制炭疽毒素LT支持小鼠中性粒细胞的关键促炎反应。
