Mechanism for the release of IL-8 from A549 cells treated with alpha-toxin.

产气荚膜梭菌（C。产气荚膜梭菌）的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边缘处的血管内皮上大量积聚。静脉注射C.将产气荚膜杆菌α-毒素导入小鼠导致中性粒细胞在肺和肝中的血管内皮上的积累，以及GRO/KC的释放。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均能抑制毒素诱导的TrkA磷酸化和IL-8的产生; K252 a还能抑制毒素诱导的ERK 1/2和p38 MAPK的磷酸化。ERK 1/2抑制剂PD 98059可抑制ERK 1/2磷酸化和NF-κB p65核转位，而p38 MAPK抑制剂SB 203580则无此作用。PD 98059和SB 203580可抑制毒素诱导的IL-8 mRNA的表达，而SB 203580则可降低毒素诱导的IL-8 mRNA的稳定性。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 on the vascular endothelium at the margins. Intravenous injection of C. perfringens alpha-toxin into mice resulted in accumulation of neutrophils on the vascular endothelium in lung and liver, and release of GRO/KC. 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 ERK1/2 and p38 MAPK. PD98059, an ERK1/2 inhibitor, depressed phosphorylation of ERK1/2 and nuclear translocation of 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.