Purinergic receptor regulation of LPS-induced signaling and pathophysiology

Guerra, Alma N.; Fisette, Philip L.; Pfeiffer, Zachary A.; Quinchia-Rios, Beatriz H.; Prabhu, Usha; Aga, Mini; Denlinger, Loren C.; Guadarrama, Arturo G.; Abozeid, Sara; Sommer, Julie A.; Proctor, Richard A.; Bertics, Paul J.

doi:10.1179/096805103225001468

Cited by 32 publications

(32 citation statements)

References 3 publications

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“…P2Y 2 , P2Y 4 and P2Y 6 receptors are also expressed by macrophages. The P2Y 2 subtype was found to promote transcription of IL-6 [177] and the coordinate action of P2Y and P2X receptors modulated LPS-induced TNF-α-, IL1-β-and NO-production [178]. In murine J774 macrophages LPS-induced COX2 upregulation and subsequent PGE 2 -stimulated iNOS induction was potentiated by UTP acting at the P2Y 6 receptor.…”

Section: Inflammation Allergies and Host Defencementioning

confidence: 98%

P2 Receptors Activated by Uracil Nucleotides - An Update

Brunschweiger¹,

Müller²

2006

CMC

134

174

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Pyrimidine nucleotides, including UTP, UDP and UDP-glucose, are important signaling molecules which activate G protein-coupled membrane receptors (GPCRs) of the P2Y family. Four distinct pyrimidine nucleotide-sensitive P2Y receptor subtypes have been cloned, P2Y2, P2Y4, P2Y6 and P2Y14. P2Y2 and P2Y4 receptors are activated by UTP (the P2Y2, and the rat but not the human P2Y4 receptor are also activated by ATP), the P2Y6 receptor is activated by UDP, and the P2Y14 receptor by UDP-glucose. Furthermore, non-P2Y GPCRs, the cysteinylleukotriene receptors (CysLT1R and CysLT2R) have been described to be activated by UDP in addition to activation by cysteinylleukotrienes. While P2Y2, P2Y4, and P2Y6 receptor activation results in stimulation of phospholipase C, the P2Y14 receptor is coupled to inhibition of adenylate cyclase. Derivatives and analogs of the physiological nucleotides UTP, UDP and ATP have been synthesized and evaluated in order to obtain enzymatically stable, subtype-selective agonists. The P2Y2 receptor agonists diuridine tetraphosphate (diquafosol) and the uracil-cytosine dinucleotide denufosol are currently undergoing clinical trials for dry eye disease, retinal detachment disease, upper respiratory tract symptoms, and cystic fibrosis, respectively. The first antagonists for P2Y2 and P2Y6 receptors that appear to be selective versus other P2Y receptor subtypes have recently been described. Selective antagonists for P2Y4 and P2Y14 receptors are still lacking. Uracil nucleotide-sensitive P2Y receptor subtypes may constitute future targets for the treatment of certain cancer types, vascular diseases, inflammatory diseases, and immunomodulatory intervention. They have also been proposed to play a role in neurodegenerative diseases. This article is an updated version of "P2-Pyrimidinergic Receptors and Their Ligands" by C. E. Müller published in Curr. Pharm. Des. 2002, 8, 2353-2369.

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Section: Inflammation Allergies and Host Defencementioning

confidence: 98%

P2 Receptors Activated by Uracil Nucleotides - An Update

Brunschweiger¹,

Müller²

2006

CMC

134

174

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“…For example, it has been observed that LPS-induced IL-1␤ release from peritoneal macrophages isolated from P2RX7 Ϫ/Ϫ mice is compromised when compared with that observed with wild-type control littermates [5]. Moreover, murine RAW 264.7 macrophages that express a nonactive form of P2RX7 have reduced LPS-induced NO release as compared with macrophages with functional P2RX7 [6]. In terms of other diseases, P2RX7 Ϫ/Ϫ mice also exhibit a reduced incidence and severity of anti-collagen-induced arthritis symptoms when compared with their littermate (P2RX7 ϩ/ϩ ) controls [7].…”

Section: Introductionmentioning

confidence: 99%

The nucleotide receptor P2RX7 mediates ATP-induced CREB activation in human and murine monocytic cells

Gavala

Pfeiffer

Bertics

2008

Journal of Leukocyte Biology

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Nucleotide receptors serve as sensors of extracellular ATP and are important for immune function. The nucleotide receptor P2RX7 is a cell-surface, ligand-gated cation channel that has been implicated in many diseases, including arthritis, granuloma formation, sepsis, and tuberculosis. These disorders are often exacerbated by excessive mediator release from activated macrophages in the inflammatory microenvironment. Although P2RX7 activation can modulate monocyte/macrophage-induced inflammatory events, the relevant molecular mechanisms are poorly understood. Previous studies suggest that MAPK cascades and transcriptional control via CREB-linked pathways regulate the inflammatory capacity of monocytic cells. As P2RX7 promotes MAPK activation and inflammatory mediator production, we examined the involvement MAPK-induced CREB activation in P2RX7 action. Our data reveal that stimulation of multiple monocytic cell lines with P2RX7 agonists induces rapid CREB phosphorylation. In addition, we observed a lack of nucleotide-induced CREB phosphorylation in RAW 264.7 cells expressing nonfunctional P2RX7 and a gain of nucleotide-induced CREB phosphorylation in human embryonic kidney-293 cells that heterologously express human P2RX7. Furthermore, our results indicate that P2RX7 agonist-induced CREB phosphorylation is partly mediated via Ca(2+) fluxes and the MEK/ERK system. Mechanistic analyses revealed that macrophage stimulation with a P2RX7 agonist induces CREB/CREB-binding protein complex formation, which is necessary for CREB transcriptional activation. Also, we demonstrate that P2RX7 activation induces a known CREB-dependent gene (c-fos) and that dominant-negative CREB constructs attenuate this response. These studies support the idea that P2RX7 stimulation can directly regulate protein expression that is not dependent on costimulation with other immune modulators such as LPS.

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“…The use of AMPs is one potentially effective approach to the treatment of MDR A. baumannii. AMPs are particularly attractive as new antimicrobial agents against MDR bacteria, including A. baumannii, because their mechanism of action, which involves permeation of the bacterial membranes, reduces the likelihood of emergence of resistance (40)(41)(42)(43)(44)(45). That said, other bacteria do exhibit mechanisms to resist AMPs (46)(47)(48).…”

Section: Effects Of Antibiotic Agents On Mdr a Baumannii Cells The 19mentioning

confidence: 99%

Synergistic Effects and Antibiofilm Properties of Chimeric Peptides against Multidrug-Resistant Acinetobacter baumannii Strains

Gopal

Kim

Lee

et al. 2014

Antimicrob Agents Chemother

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fThe increasing prevalence of drug-resistant pathogens highlights the need to identify novel antibiotics. Here we investigated the efficacies of four new antimicrobial peptides (AMPs) for potential drug development. The antibacterial activities, synergistic effects, and antibiofilm properties of the four chimeric AMPs were tested against Acinetobacter baumannii, an emerging Gramnegative, nosocomial, drug-resistant pathogen. Nineteen A. baumannii strains resistant to ampicillin, cefotaxime, ciprofloxacin, tobramycin, and erythromycin were isolated at a hospital from patients with cholelithiasis. All four peptides exhibited significant antibacterial effects (MIC ‫؍‬ 3.12 to 12.5 M) against all 19 strains, whereas five commercial antibiotics showed little or no activity against the same pathogens. An exception was polymyxin, which was effective against all of the strains tested. Each of the peptides showed synergy against one or more strains when administered in combination with cefotaxime, ciprofloxacin, or erythromycin. The peptides also exhibited an ability to prevent biofilm formation, which was not seen with cefotaxime, ciprofloxacin, or erythromycin, though polymyxin also inhibited biofilm formation. Indeed, when administered in combination with ciprofloxacin, the AMP HPMA exerted a potent synergistic effect against A. baumannii biofilm formation. Collectively, our findings indicate that the AMPs tested have no cytotoxicity but possess potent antibacterial and antibiofilm activities and may act synergistically with commercial antibiotics.

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Purinergic receptor regulation of LPS-induced signaling and pathophysiology

Cited by 32 publications

References 3 publications

P2 Receptors Activated by Uracil Nucleotides - An Update

P2 Receptors Activated by Uracil Nucleotides - An Update

The nucleotide receptor P2RX7 mediates ATP-induced CREB activation in human and murine monocytic cells

Synergistic Effects and Antibiofilm Properties of Chimeric Peptides against Multidrug-Resistant Acinetobacter baumannii Strains

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