Macrophage paraoxonase 2 (PON2) expression is up-regulated by pomegranate juice phenolic anti-oxidants via PPARγ and AP-1 pathway activation

Shiner, Maayan; Fuhrman, Bianca; Aviram, Michael

doi:10.1016/j.atherosclerosis.2007.01.007

Cited by 100 publications

(79 citation statements)

References 30 publications

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“…Our data show that phagocytosis and bacterial clearance were significantly augmented by PPAR␥ agonists in macrophages in vitro and in the lungs of mice infected with PAO1 in vivo. Our data establish that the immunostimulatory effects of PPAR␥ are partially mediated through the induction of PON-2, a downstream target of PPAR␥ (29). Furthermore, our data show that PPAR␥ and PON-2 expression is attenuated when cells are infected with PAO1 or 3-oxo-C 12 -HSL but not with the lasI QS mutant strains of PAO1 (47).…”

Section: Discussionsupporting

confidence: 52%

“…Regulation of PON-2 in macrophages by PPAR␥ agonists has been previously established by Shiner et al However, their study was conducted in an atherosclerosis model, whereby PON-2 was induced by polyphenolic antioxidants in pomegranate juice, in a PPAR␥-and AP-1-dependent manner (29).…”

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confidence: 98%

“…Based on these observations, THP-1 cells were transfected with To further confirm our findings, we used a natural activator of PPAR␥, magnolol (29,30). Macrophages were treated with vehicle or 5 M magnolol.…”

Section: Ppar␥ Agonists Enhanced Phagocytosis and Bacterial Clearancementioning

confidence: 99%

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Enhanced Clearance of Pseudomonas aeruginosa by Peroxisome Proliferator-Activated Receptor Gamma

et al. 2016

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fThe pathogenic profile of Pseudomonas aeruginosa is related to its ability to secrete a variety of virulence factors. Quorum sensing (QS) is a mechanism wherein small diffusible molecules, specifically acyl-homoserine lactones, are produced by P. aeruginosa to promote virulence. We show here that macrophage clearance of P. aeruginosa (PAO1) is enhanced by activation of the nuclear hormone receptor peroxisome proliferator-activated receptor gamma (PPAR␥). Macrophages treated with a PPAR␥ agonist (pioglitazone) showed enhanced phagocytosis and bacterial killing of PAO1. It is known that PAO1 QS molecules are inactivated by PON-2. QS molecules are also known to inhibit activation of PPAR␥ by competitively binding PPAR␥ receptors. In accord with this observation, we found that infection of macrophages with PAO1 inhibited expression of PPAR␥ and PON-2. Mechanistically, we show that PPAR␥ induces macrophage paraoxonase 2 (PON-2), an enzyme that degrades QS molecules produced by P. aeruginosa. Gene silencing studies confirmed that enhanced clearance of PAO1 in macrophages by PPAR␥ is PON-2 dependent. Further, we show that PPAR␥ agonists also enhance clearance of P. aeruginosa from lungs of mice infected with PAO1. Together, these data demonstrate that P. aeruginosa impairs the ability of host cells to mount an immune response by inhibiting PPAR␥ through secretion of QS molecules. These studies define a novel mechanism by which PPAR␥ contributes to the host immunoprotective effects during bacterial infection and suggest a role for PPAR␥ immunotherapy for P. aeruginosa infections.

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Section: Discussionsupporting

confidence: 52%

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confidence: 98%

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Enhanced Clearance of Pseudomonas aeruginosa by Peroxisome Proliferator-Activated Receptor Gamma

et al. 2016

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“…However, paradoxically, Stoltz et al also observed that the rates of inactivation of 3OC12-HSL in intact PON2-deficient and wild-type cells were the same (38). Recent studies have demonstrated the localization of PON2 to the endoplasmic reticulum and nuclear envelope, but not the plasma membrane, in murine macrophages and a number of human cell lines (16,35), which suggests that PON2 3OC12-HSL inactivation likely occurs intracellularly. This is consistent with the suggestion by Stoltz et al that transport of 3OC12-HSL into the cells may be rate limiting for inactivation and that PON1 and/or PON3 are present at levels high enough to rapidly inactivate the 3OC12-HSL that enters the PON2-deficient cells.…”

Section: Discussionmentioning

confidence: 99%

Dominant Role of Paraoxonases in Inactivation of the Pseudomonas aeruginosa Quorum-Sensing Signal N -(3-Oxododecanoyl)- l -Homoserine Lactone

et al. 2008

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The pathogenic bacterium Pseudomonas aeruginosa causes serious infections in immunocompromised patients. N-(3-Oxododecanoyl)-L-homoserine lactone (3OC12-HSL) is a key component of P. aeruginosa's quorum-sensing system and regulates the expression of many virulence factors. 3OC12-HSL was previously shown to be hydrolytically inactivated by the paraoxonase (PON) family of calcium-dependent esterases, consisting of PON1, PON2, and PON3. Here we determined the specific activities of purified human PONs for 3OC12-HSL hydrolysis, including the common PON1 polymorphic forms, and found they were in the following order: PON2 Ͼ Ͼ PON1 192R > PON1 192Q > PON3. PON2 exhibited a high specific activity of 7.6 ؎ 0.4 mols/min/mg at 10 M 3OC12-HSL, making it the best PON2 substrate identified to date. By use of class-specific inhibitors, approximately 85 and 95% of the 3OC12-HSL lactonase activity were attributable to PON1 in mouse and human sera, respectively. In mouse liver homogenates, the activity was metal dependent, with magnesium-and manganese-dependent lactonase activities comprising 10 to 15% of the calcium-dependent activity. In mouse lung homogenates, all of the activity was calcium dependent. The calcium-dependent activities were irreversibly inhibited by extended EDTA treatment, implicating PONs as the major enzymes inactivating 3OC12-HSL. In human HepG2 and EA.hy 926 cell lysates, the 3OC12-HSL lactonase activity closely paralleled the PON2 protein levels after PON2 knockdown by small interfering RNA treatment of the cells. These findings suggest that PONs, particularly PON2, could be an important mechanism by which 3OC12-HSL is inactivated in mammals.Pseudomonas aeruginosa is an opportunistic bacterium which causes serious infections in immunocompromised and cystic fibrosis patients (10). As with many gram-negative bacteria, P. aeruginosa produces acyl-homoserine lactone (AHL) quorumsensing (QS) signaling molecules termed autoinducers which allow the single-celled organisms to coordinate their actions (36). N-(3-Oxododecanoyl)-L-homoserine lactone (3OC12-HSL) is a key autoinducer synthesized by P. aeruginosa which regulates the expression of extracellular virulence factors and biofilm formation (5, 36). Rats and mice experimentally infected with P. aeruginosa mutants deficient in the ability to produce or respond to 3OC12-HSL exhibited significantly diminished lung pathology, bacterial dissemination, and morbidity and accelerated bacterial clearance compared to animals infected with wild-type bacteria, demonstrating the importance of 3OC12-HSL for P. aeruginosa pathogenicity (14,21,27,31,40). 3OC12-HSL also has an array of immunomodulatory effects on eukaryotic cells, including the induction of apoptosis, inhibition of leukocyte proliferation, activation of neutrophils and macrophages, and induction of proinflammatory mediators (7,15,34,37,39,43). Recently, it was shown that a number of mammalian cell lines were able to inactive 3OC12-HSL (5), providing a possible mechanism for reduction of bacterial virulence.Mam...

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“…Macrophage oxidative stress was shown to affect PON2 expression and activities in a biphasic U-shape pattern (14,20). Upregulation of macrophage PON2 was shown to occur via several mechanisms, including NADPH-oxidase activation (21), pomegranate juice polyphenolic antioxidants (22), unesterified cholesterol accumulation (23), and urokinase plasminogen activator (24).…”

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confidence: 99%

Paraoxonase 2 attenuates macrophage triglyceride accumulation via inhibition of diacylglycerol acyltransferase 1

Rosenblat

Coleman

Reddy

et al. 2009

Journal of Lipid Research

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This study questioned the role of paraoxonase 2 (PON2) in attenuation of macrophage lipids accumulation. Mouse peritoneal macrophages (MPMs) harvested from PON2-deficient mice versus control C57BL/6 mice, look like foam cells and were larger in size and filled with lipid droplets. Macrophage triglyceride (but not cholesterol) content, biosynthesis rate, and microsomal acyl-CoA:diacylglycerol acyltransferase 1 (DGAT1) activity (not mRNA and protein) in PON2-deficient versus control MPM were all significantly increased by 4.6-, 3.6-, and 4.4-fold, respectively. Similarly, microsomal DGAT1 activity and cellular triglyceride content were significantly decreased in human PON2-transfected cells as well as upon incubation of PON2-deficient MPM with recombinant PON2. In all the above experimental systems, PON2 also decreased macrophage oxidative state. Incubation of PON2-deficient MPM with the free radicals generator 2,2′-amidinopropane hydrochloride increased cellular oxidative stress and DGAT1 activity by 2.2-and 3.4-fold, respectively, whereas incubation of microsomes from PON2-deficient MPM with superoxide dismutase decreased DGAT1 activity by 40%. We thus conclude that PON2 attenuates macrophage triglyceride accumulation and foam cell formation via inhibition of microsomal DGAT1 activity, which appears to be sensitive to oxidative state.-Rosenblat, M., R. Coleman, S. T. Reddy, and M. Aviram. Paraoxonase 2 attenuates macrophage triglyceride accumulation via inhibition of diacylglycerol acyltransferase 1. J. Lipid Res. 2009. 50: 870-879.

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Macrophage paraoxonase 2 (PON2) expression is up-regulated by pomegranate juice phenolic anti-oxidants via PPARγ and AP-1 pathway activation

Cited by 100 publications

References 30 publications

Enhanced Clearance of Pseudomonas aeruginosa by Peroxisome Proliferator-Activated Receptor Gamma

Enhanced Clearance of Pseudomonas aeruginosa by Peroxisome Proliferator-Activated Receptor Gamma

Dominant Role of Paraoxonases in Inactivation of the Pseudomonas aeruginosa Quorum-Sensing Signal N -(3-Oxododecanoyl)- l -Homoserine Lactone

Paraoxonase 2 attenuates macrophage triglyceride accumulation via inhibition of diacylglycerol acyltransferase 1

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