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.

白介素（IL）-1β对于广泛的炎症反应至关重要。先前，我们报道IL-1β是通过NF-κB和JNK途径响应铜绿假单胞菌衍生的DnaK而产生的。但是，与维持IL-1β动态平衡过程相反的信号途径尚不清楚。在这里，我们显示了DnaK介导的IL1β表达阻断PI3K / PDK1后，巨噬细胞中的TNF-α明显增加。通过测量释放的IL-1β蛋白可以证实这一点。PI3K对IL-1β产生的负面影响取决于抑制NF-κB和JNK激活。有趣的是，PDK1（PI3K的潜在介体）充当了NF-κB激活的上游调节剂，但下调了JNK的激活。此外，IL-1β的产生和JNK的激活是由磷酸化的FoxO1的抑制触发的。FoxO1的磷酸化受PD​​K1信号响应DnaK的控制。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。