Negative regulation of interleukin 1 beta expression in response to DnaK from Pseudomonas aeruginosa via the PI3K/PDK1/FoxO1 pathways

Abstract

Interleukin (IL)-1 beta is crucial for a wide range of inflammatory responses. Previously, we reported that IL-1 beta is produced in response to Pseudomonas aeruginosa-derived DnaK via NF-kappa B and JNK pathways; however, the signaling pathways that counter the process to maintain IL-1 beta homeostasis are unknown. Here, we show that DnaK-mediated expression of IL1 beta is increased markedly in macrophages upon blockade of PI3K/PDK1. This was verified by measuring released IL-1 beta protein. The negative effect of PI3K on IL-1 beta production was dependent on suppression of both NF-kappa B and JNK activation. Intriguingly, PDK1 (an underlying mediator of PI3K) acted as an upstream regulator for the activation of NF-kappa B, but downregulated JNK activation. Furthermore, production of IL-1 beta 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-1 beta production is modulated by P. aeruginosaderived DnaK via cross-talk between JNK and PI3K/PDK1/FoxO1 pathways.