Department of Biotechnology and Bioinformatics, Korea University, Sejong 30019, Republic of Korea.
State Key Laboratory of Medicinal Chemical Biology, Key Laboratory of Molecular Microbiology and Technology of the Ministry of Education, Department of Microbiology, Nankai University, Tianjin 300071, China.
Comp Immunol Microbiol Infect Dis. 2020 Dec;73:101543. doi: 10.1016/j.cimid.2020.101543. Epub 2020 Sep 9.
Interleukin (IL)-1β is crucial for a wide range of inflammatory responses. Previously, we reported that IL-1β is produced in response to Pseudomonas aeruginosa-derived DnaK via NF-κB and JNK pathways; however, the signaling pathways that counter the process to maintain IL-1β homeostasis are unknown. Here, we show that DnaK-mediated expression of IL1β is increased markedly in macrophages upon blockade of PI3K/PDK1. This was verified by measuring released IL-1β protein. The negative effect of PI3K on IL-1β production was dependent on suppression of both NF-κB and JNK activation. Intriguingly, PDK1 (an underlying mediator of PI3K) acted as an upstream regulator for the activation of NF-κB, but downregulated JNK activation. Furthermore, production of IL-1β and activation of JNK were triggered by inhibition of phosphorylated FoxO1; phosphorylation of FoxO1 was controlled by PDK1 signaling in response to DnaK. Thus, IL-1β production is modulated by P. aeruginosa-derived DnaK via cross-talk between JNK and PI3K/PDK1/FoxO1 pathways.
白细胞介素 (IL)-1β 对于广泛的炎症反应至关重要。此前，我们报告称，IL-1β 是在 NF-κB 和 JNK 途径下，对铜绿假单胞菌衍生的 DnaK 作出反应而产生的；然而，对抗该过程以维持 IL-1β 体内平衡的信号通路尚不清楚。在这里，我们发现，在 PI3K/PDK1 被阻断后，巨噬细胞中 DnaK 介导的 IL1β 表达明显增加。通过测量释放的 IL-1β 蛋白可以验证这一点。PI3K 对 IL-1β 产生的负作用依赖于 NF-κB 和 JNK 激活的抑制。有趣的是，PDK1（PI3K 的潜在介质）作为 NF-κB 激活的上游调节剂，但下调了 JNK 激活。此外，IL-1β 的产生和 JNK 的激活是由磷酸化 FoxO1 的抑制触发的；FoxO1 的磷酸化受到 PDK1 信号的控制，以响应 DnaK。因此，铜绿假单胞菌衍生的 DnaK 通过 JNK 和 PI3K/PDK1/FoxO1 途径之间的串扰来调节 IL-1β 的产生。
