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

产气荚膜梭菌(C。产气荚膜增生是指感染区域内中性粒细胞的缺失和中性粒细胞在边缘血管内皮上的大量积聚。静脉注射产气荚膜梭菌α毒素可引起小鼠肺、肝血管内皮中性粒细胞聚集，GRO/KC释放。在A549细胞中，α毒素触发信号转导通路的激活，导致mRNA的表达和IL-8的产生，从而激活中性粒细胞的迁移和结合。酪氨酸激酶a （TrkA）抑制剂K252a和TrkA的siRNA抑制毒素诱导的TrkA磷酸化和IL-8的产生。此外，K252a抑制毒素诱导的ERK1/2和p38 MAPK的磷酸化。ERK1/2抑制剂PD98059抑制ERK1/2的磷酸化和NF-κB p65的核易位，而p38 MAPK抑制剂SB203580则没有作用。另一方面，PD98059和SB203580抑制了毒素诱导的IL-8的产生。PD98059可抑制毒素诱导的IL-8 mRNA表达，SB203580可降低IL-8 mRNA的稳定性。这些结果表明，α -毒素通过激活ERK1/2/NF-κB和p38 MAPK两种不同的途径诱导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.