Clostridium perfringens alpha-toxin induces the release of IL-8 through a dual pathway via TrkA in A549 cells.
Clostridium perfringens alpha-toxin induces the release of IL-8 through a dual pathway via TrkA in A549 cells.
复制标题
产气荚膜梭菌 α 毒素通过 A549 细胞中的 TrkA 双重途径诱导 IL-8 的释放。
DOI：
10.1016/j.bbadis.2012.06.007
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发表时间：
2012
期刊：
影响因子：
--
通讯作者：
Sakurai J
中科院分区：
文献类型：
--
作者：
Oda M;Shiihara R;Ohmae Y;Kabura M;Takagishi T;Kobayashi K;Nagahama M;Inoue M;Abe T;Setsu K;Sakurai J
产气荚膜梭菌（C。产气荚膜梭菌）的另一个特征是感染区域内缺乏嗜中性粒细胞，并且嗜中性粒细胞在坏死区域边缘周围的血管内皮处大量积聚。静脉注射C.将产气荚膜杆菌α-毒素导入小鼠导致嗜中性粒细胞在肺和肝中的血管内皮处积聚，并释放GRO/KC，GRO/KC是与人白细胞介素-8（IL-8）同源的CXC趋化因子家族的成员。α-毒素触发信号转导途径的激活，导致mRNA表达和IL-8的产生，其激活A549细胞中中性粒细胞的迁移和结合。酪氨酸激酶A（TrkA）抑制剂K252 a和针对TrkA的siRNA抑制毒素诱导的TrkA磷酸化和IL-8的产生。此外，K252 a抑制毒素诱导的细胞外调节激酶1/2（ERK 1/2）和p38丝裂原活化蛋白激酶（MAPK）的磷酸化。ERK 1/2抑制剂PD 98059可抑制ERK 1/2的磷酸化和核因子κ B（NF-κB）p65的核转位，而p38 MAPK抑制剂SB 203580则无此作用。另一方面，PD 98059和SB 203580抑制毒素诱导的IL-8的产生。用PD 98059处理细胞导致毒素诱导的IL-8 mRNA表达的抑制，用SB 203580处理导致IL-8 mRNA稳定性的降低。这些结果表明，α-毒素通过激活ERK 1/2/NF-κB和p38 MAPK两条独立途径诱导IL-8的产生。
A characteristic feature of gas gangrene with Clostridium perfringens (C. perfringens) is the absence of neutrophils within the infected area and the massive accumulation of neutrophils at the vascular endothelium around the margins of the necrotic region. Intravenous injection of C. perfringens alpha-toxin into mice resulted in the accumulation of neutrophils at the vascular endothelium in lung and liver, and release of GRO/KC, a member of the CXC chemokine family with homology to human interleukin-8 (IL-8). Alpha-toxin triggered activation of signal transduction pathways causing mRNA expression and production of IL-8, which activates migration and binding of neutrophils, in A549 cells. K252a, a tyrosine kinase A (TrkA) inhibitor, and siRNA for TrkA inhibited the toxin-induced phosphorylation of TrkA and production of IL-8. In addition, K252a inhibited the toxin-induced phosphorylation of extracellular regulated kinase 1/2 (ERK1/2) and p38 mitogen-activated protein kinase (MAPK). PD98059, an ERK1/2 inhibitor, depressed phosphorylation of ERK1/2 and nuclear translocation of nuclear factor kappa B (NF-κB) p65, but SB203580, a p38 MAPK inhibitor, did not. On the other hand, PD98059 and SB203580 suppressed the toxin-induced production of IL-8. Treatment of the cells with PD98059 resulted in inhibition of IL-8 mRNA expression induced by the toxin and that with SB203580 led to a decrease in the stabilization of IL-8 mRNA. These results suggest that alpha-toxin induces production of IL-8 through the activation of two separate pathways, the ERK1/2/NF-κB and p38 MAPK pathways.