Paraoxonase-2 Modulates Stress Response of Endothelial Cells to Oxidized Phospholipids and a Bacterial Quorum–Sensing Molecule

Kim, Juyong Brian; Xia, Yu‐Rong; Romanoski, Casey E.; Lee, Sangderk; Meng, Yan; Shi, Yi-Shou; Bourquard, Noam; Gong, KeWei; Port, Zachary; Grijalva, Víctor; Reddy, Srinivasa T.; Berliner, Judith A.; Lusis, Aldons J.; Shih, Diana M.

doi:10.1161/atvbaha.111.232827

Cited by 34 publications

(32 citation statements)

References 43 publications

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“…PON2 is expressed intracellularly, is widely found in mammalian tissues and cell types, and efficiently hydrolyzes 3OC12 to 3OC12 acid (20)(21)(22)(23)(24)(25). Independent of its hydrolytic activity, PON2 also has antioxidant activity and can protect cells from endoplasmic reticulum (ER) stress, including ER stress induced by 3OC12 (22,23,26).…”

mentioning

confidence: 99%

Novel Paraoxonase 2-Dependent Mechanism Mediating the Biological Effects of the Pseudomonas aeruginosa Quorum-Sensing Molecule N -(3-Oxo-Dodecanoyl)- l -Homoserine Lactone

et al. 2015

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cPseudomonas aeruginosa produces N-(3-oxo-dodecanoyl)-L-homoserine lactone (3OC12), a crucial signaling molecule that elicits diverse biological responses in host cells thought to subvert immune defenses. The mechanism mediating many of these responses remains unknown. The intracellular lactonase paraoxonase 2 (PON2) hydrolyzes and inactivates 3OC12 and is therefore considered a component of host cells that attenuates 3OC12-mediated responses. Here, we demonstrate in cell lines and in primary human bronchial epithelial cells that 3OC12 is rapidly hydrolyzed intracellularly by PON2 to 3OC12 acid, which becomes trapped and accumulates within the cells. Subcellularly, 3OC12 acid accumulated within the mitochondria, a compartment where PON2 is localized. Treatment with 3OC12 caused a rapid PON2-dependent cytosolic and mitochondrial pH decrease, calcium release, and phosphorylation of stress signaling kinases. The results indicate a novel, PON2-dependent intracellular acidification mechanism by which 3OC12 can mediate its biological effects. Thus, PON2 is a central regulator of host cell responses to 3OC12, acting to decrease the availability of 3OC12 for receptor-mediated effects and acting to promote effects, such as calcium release and stress signaling, via intracellular acidification. P seudomonas aeruginosa is a common pathogen causing serious infections in immunocompromised and ill individuals due to the bacteria's ability to evade host immune responses and acquire antibiotic resistance (1). Many Gram-negative bacteria, including P. aeruginosa, produce acyl-homoserine lactone (AHL) signaling molecules which regulate the cell density-dependent expression of virulence factors in a process termed quorum sensing (QS) (1). The AHL N-(3-oxododecanoyl)-L-homoserine lactone (3OC12) is a key P. aeruginosa QS signal that has been shown to be necessary for biofilm maturation and full expression of virulence in P. aeruginosa animal infection models (2-5). Concentrations up to 600 M 3OC12 have been measured in P. aeruginosa biofilms in vitro (6). Concentrations of over 6 M 3OC12 have been detected in the sputum of individuals with pulmonary P. aeruginosa infections (7), suggesting active 3OC12 signaling in the human disease as well.In addition to modulating bacterial gene expression, 3OC12 elicits a multitude of biological responses in diverse mammalian cell types (8). Depending upon the cell type and dose, 3OC12 (10 to 100 M) can induce apoptosis, endoplasmic reticulum (ER) stress, chemotaxis, and proinflammatory gene expression (8-10). Conversely, 3OC12 inhibited lipopolysaccharide (LPS) induction of proinflammatory mediators in macrophages, fibroblasts, and epithelial cells and in vivo by repressing nuclear factor -light chain enhancer of activated B-cell (NF-B) signaling (11). In antigen-stimulated T-lymphocytes, 3OC12 inhibits cell proliferation and production of gamma interferon and interleukin-4 (IL-4), critical regulators of immunity (8,12). These diverse responses suggest that 3OC12 acts through multiple, and cell-...

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mentioning

confidence: 99%

Novel Paraoxonase 2-Dependent Mechanism Mediating the Biological Effects of the Pseudomonas aeruginosa Quorum-Sensing Molecule N -(3-Oxo-Dodecanoyl)- l -Homoserine Lactone

et al. 2015

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“…Kim et al (20) confirmed that 50 µM 3-oxo-C12-HSL effectively induces UPR and activates UPR target genes, such as C/EBP β and CHOP in HAECs. Therefore, the mRNA expression of representative target genes of UPR activation, such as C/EBP β and CHOP, was analyzed using qRT-PCR to determine whether 6.25 µM 3-oxo-C12-HSL was able to efficiently activate these genes ( Fig.…”

Section: Resultsmentioning

confidence: 96%

“…Recent studies demonstrated that UPR-mediated induction of CHOP reduces inflammatory cytokine secretion and NF-κB activation (18,19). A recent study also demonstrated that 3-oxo-C12-HSL may induce the expression of UPR genes, such as C/EBP β and CHOP, in human aortic endothelial cells (HAECs) (20). These data strongly indicate that 3-oxo-C12-HSL may inhibit NF-κB activity through the induction of UPR.…”

Section: Introductionmentioning

confidence: 87%

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

Zhang

Gong

et al. 2014

Biomedical Reports

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N-3-oxododecanoyl homoserine lactone (3-oxo-C12-HSL), a quorum-sensing signal molecule produced by , 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 evades the host immune system and maintains a persistent infection.

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“…Contrary to the literature, the paroxinase PON2 was not expressed in lower levels in the airways of non-CF bronchiectasis subjects in this study. PON2 degrades 3-oxo-C12-HSL via lactonlysis [112].…”

Section: Discussionmentioning

confidence: 99%

“…3-oxo-C12-HSL [108] and PQS [109] act on the NFκB pathway in a number of postulated ways, dependent upon the cell type and type of cellular stimulation. Interference with IκB, inhibition of peroxisome proliferator-activated receptor gamma (PPARγ) [111] and interference with host protein translation via induction of the unfolded protein response [112] are all mechanisms by which 3-oxo-C12-HSL may modulate responses in mammalian cells.…”

Section: Cell Culturementioning

confidence: 99%

An investigation into the effect of erythromycin on Pseudomonas aeruginosa quorum sensing in non-cystic fibrosis bronchiectasis

Burr¹

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Paraoxonase-2 Modulates Stress Response of Endothelial Cells to Oxidized Phospholipids and a Bacterial Quorum–Sensing Molecule

Cited by 34 publications

References 43 publications

Novel Paraoxonase 2-Dependent Mechanism Mediating the Biological Effects of the Pseudomonas aeruginosa Quorum-Sensing Molecule N -(3-Oxo-Dodecanoyl)- l -Homoserine Lactone

Novel Paraoxonase 2-Dependent Mechanism Mediating the Biological Effects of the Pseudomonas aeruginosa Quorum-Sensing Molecule N -(3-Oxo-Dodecanoyl)- l -Homoserine Lactone

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

An investigation into the effect of erythromycin on Pseudomonas aeruginosa quorum sensing in non-cystic fibrosis bronchiectasis

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