Pseudomonas aeruginosa quorum-sensing molecule N-(3-oxododecanoyl) homoserine lactone attenuates lipopolysaccharide-induced inflammation by activating the unfolded protein response

N-3-oxododecanoyl homoserine lactone (3-oxo-C12-HSL), a quorum-sensing signal molecule produced by Pseudomonas aeruginosa (P. aeruginosa) , is involved in the expression of bacterial virulence factors and in the modulation of host immune responses by directly disrupting nuclear factor-κB (NF-κB) signaling and inducing cell apoptosis. The unfolded protein response (UPR) triggered by endoplasmic reticulum (ER) stress may suppress inflammatory responses in the later phase by blocking NF-κB activation. It was recently demonstrated that 3-oxo-C12-HSL may induce UPR in human aortic endothelial cells (HAECs). Therefore, 3-oxo-C12-HSL may also inhibit NF-κB activation and suppress inflammatory responses by activating UPR. However, the possible underlying mechanism has not been fully elucidated. Accordingly, we investigated the effects of 3-oxo-C12-HSL on cellular viability, UPR activation, lipopolysaccharide (LPS)-induced NF-κB activation and inflammatory response in the RAW264.7 mouse macrophage cell line. Treatment with 6.25 μM 3-oxo-C12-HSL was not found to affect the viability of RAW264.7 cells. However, pretreating RAW264.7 cells with 6.25 μM 3-oxo-C12-HSL effectively triggered UPR and increased the expression of UPR target genes, such as CCAAT/enhancer-binding protein β (C/EBP β) and CCAAT/enhancer-binding protein-homologous protein (CHOP). The expression of C/EBP β and CHOP was found to be inversely correlated with LPS-induced NF-κB activation. 3-Oxo-C12-HSL pretreatment was also shown to inhibit LPS-stimulated proinflammatory cytokine production. Hence, 3-oxo-C12-HSL may attenuate LPS-induced inflammation via UPR-mediated NF-κB inhibition without affecting cell viability. This may be another mechanism through which P. aeruginosa evades the host immune system and maintains a persistent infection.