P2Y11 Receptors: Properties, Distribution and Functions

Kennedy, Charles

doi:10.1007/5584_2017_89

Cited by 36 publications

(55 citation statements)

References 65 publications

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“…20 It should be noted that the gene for the P2Y11 receptor does not appear to be present in the rodent genome, which hampers the development of our knowledge and understanding of its properties and functions. 21 In this study, our results indicate that antagonism of the P2Y11 receptor prevented activation of the transcriptional factor NF-κB. However, it remains unknown whether NF-κB could drive the transcription of the P2Y11 receptor.…”

Section: Discussionsupporting

confidence: 51%

“…Activated FLS and other immune cells in the joint space invade and degrade the cartilage matrix by local production of cytokines, inflammatory mediators, and proteolytic enzymes . It should be noted that the gene for the P2Y11 receptor does not appear to be present in the rodent genome, which hampers the development of our knowledge and understanding of its properties and functions . In this study, our results indicate that antagonism of the P2Y11 receptor prevented activation of the transcriptional factor NF‐κB.…”

Section: Discussionmentioning

confidence: 68%

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P2Y11 receptor antagonist NF340 ameliorates inflammation in human fibroblast‐like synoviocytes: An implication in rheumatoid arthritis

Gao

2019

IUBMB Life

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Rheumatoid arthritis is a common chronic inflammatory joint disease. Fibroblast‐like synoviocytes‐mediated inflammation is closely associated with the development of rheumatoid arthritis. In this study, we report that P2Y11 receptor activity is required for cytokine‐induced inflammation in primary fibroblast‐like synoviocytes (FLS). P2Y11R is fairly expressed in primary FLS isolated from healthy subjects and is elevated to around three‐ to four‐fold in rheumatoid arthritis‐derived FLS. The expression of P2Y11R is inducible upon IL‐1β treatment. Blockage of P2Y11R by its antagonist suppresses IL‐1β‐induced TNF‐α and IL‐6 induction and ameliorates oxidative stress as determined by levels of cellular ROS and the oxidative byproduct 4‐HNE. Moreover, blockage of P2Y11R by NF340 inhibits IL‐1β‐induced matrix metalloproteinase protein expression as indicated by the levels of MMP‐1, MMP‐3, and MMP‐13. Mechanistically, blockage of P2Y11R mitigates IL‐1β‐activated NFκB signaling, which was revealed by reduced IκBα phosphorylation, nuclear p65 accumulation, and NFκB promoter activity. Our study provides evidence of a protective mechanism of P2Y11R antagonist NF340 against cytokine‐induced inflammation. Therefore, targeting P2Y11R could have potential therapeutic implication in the treatment of RA.

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Section: Discussionsupporting

confidence: 51%

Section: Discussionmentioning

confidence: 68%

P2Y11 receptor antagonist NF340 ameliorates inflammation in human fibroblast‐like synoviocytes: An implication in rheumatoid arthritis

Gao

2019

IUBMB Life

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“…In contrast to mice, CD39 expression on human CD4 T cells is largely restricted to memory T regs ( 108 ), and T cell inhibition by adenosine receptor-dependent pathways seems to be less important in humans than in mice ( 109 ). Interestingly, mice and other rodents do not possess P2Y11 receptors ( 110 ). Thus, mouse models cannot fully reflect human disease processes.…”

Section: Resultsmentioning

confidence: 99%

Mitochondria Synergize With P2 Receptors to Regulate Human T Cell Function

Ledderose

Junger

2020

Front. Immunol.

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Intracellular ATP is the universal energy carrier that fuels many cellular processes. However, immune cells can also release a portion of their ATP into the extracellular space. There, ATP activates purinergic receptors that mediate autocrine and paracrine signaling events needed for the initiation, modulation, and termination of cell functions. Mitochondria contribute to these processes by producing ATP that is released. Here, we summarize the synergistic interplay between mitochondria and purinergic signaling that regulates T cell functions. Specifically, we discuss how mitochondria interact with P2X1, P2X4, and P2Y11 receptors to regulate T cell metabolism, cell migration, and antigen recognition. These mitochondrial and purinergic signaling mechanisms are indispensable for host immune defense. However, they also represent an Achilles heel that can render the host susceptible to infections and inflammatory disorders. Hypoxia and mitochondrial dysfunction deflate the purinergic signaling mechanisms that regulate T cells, while inflammation and tissue damage generate excessive systemic ATP levels that distort autocrine purinergic signaling and impair T cell function. An improved understanding of the metabolic and purinergic signaling mechanisms that regulate T cells may lead to novel strategies for the diagnosis and treatment of infectious and inflammatory diseases.

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“…Extracellular NAD + is an agonist of P2Y purinergic receptors [14,30]; these G protein-coupled receptors are linked to the activation of PLC followed by generation of the second messengers inositol 1,4,5-triphosphate (IP 3 ) and diacylglycerol (DAG) [31]. NAD + /P2Y receptors transfer signals through PLC [19,32]. Purinergic receptors are required for extracellular NAD + and evoke biological responses, which suggests that extracellular NAD + may be sensed by cell-surface receptors.…”

Section: Discussionmentioning

confidence: 99%

Exogenous NAD+ Stimulates MUC2 Expression in LS 174T Goblet Cells via the PLC-Delta/PTGES/PKC-Delta/ERK/CREB Signaling Pathway

Yeom

Lim

2020

Biomolecules

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Background: MUC2, a major component of the mucus layer in the intestine, is associated with antimicrobial activity and gut immune system function. Currently, mucin is mainly known for its critical function in defense against toxic molecules and pathogens. In this study, we investigated the stimulatory effects of exogenous nicotinamide adenine dinucleotide (NAD + ) on the expression of MUC2 in LS 174T goblet cells. Methods: Genes related to MUC2 synthesis were measured by quantitative real-time PCR (qPCR). To analyze the gene expression profiles of NAD + -treated LS 174T goblet cells, RNA sequencing was performed. MUC2 expression in the cells and secreted MUC2 were measured by immunocytochemistry (ICC) and ELISA, respectively. Results: NAD + significantly stimulated MUC2 expression at mRNA and protein levels and increased the secretion of MUC2. Through RNA sequencing, we found that the expression of genes involved in arachidonic acid metabolism increased in NAD + -treated cells compared with the negative control cells. NAD + treatment increased phospholipase C (PLC)-δ and prostaglandin E synthase (PTGES) expression, which was inhibited by the appropriate inhibitors. Among the protein kinase C (PKC) isozymes, PKC-δ was involved in the increase in MUC2 expression. In addition, extracellular signal-regulated kinase (ERK)1/2 and cyclic AMP (cAMP) response element-binding protein (CREB) transcript levels were higher in NAD + -treated cells than in the negative control cells, and the enhanced levels of phosphorylated CREB augmented MUC2 expression. Conclusions: Exogenous NAD + increases MUC2 expression by stimulating the PLC-δ/PTGES/PKC-δ/ERK/CREB signaling pathway.Biomolecules 2020, 10, 580 2 of 18 contribute to chronic inflammation in the intestine [3]. Therefore, conservation of an intact mucus layer that properly regulates immune responses is a main factor that is necessary for the maintenance of intestinal homeostasis and the prevention of intestinal inflammatory diseases.MUC2 gene expression is regulated by cyclic AMP (cAMP) response element-binding protein (CREB) in retinoic acid-treated normal human tracheobronchial epithelial (NHTBE) cells [4]. CREB is a transcription factor regulating the expression of genes involved in a variety of cellular processes, such as cell growth and survival, differentiation, and mucin production [5]. Upon cAMP-induced phosphorylation through intracellular signaling cascades, CREB is activated and stimulates gene transcription by binding to the promoters of target genes. CREB phosphorylation through the mitogen-activated protein kinase (MAPK) signaling pathway is associated with various human diseases [5]. For example, angiotensin II induces cardiac fibrosis by enhancing periostin expression via the p38 MAPK-CREB pathway [6]. The protein kinase C (PKC)/p38 MAPK/CREB pathway is involved in membrane wound repair [7]. An E3 ubiquitin ligase (CUL4A) promotes the proliferation of cancer cells through the phosphorylation-mediated activation of ERK1/2 followed by CREB [8]. Paeoniflorin, der...

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P2Y11 Receptors: Properties, Distribution and Functions

Cited by 36 publications

References 65 publications

P2Y11 receptor antagonist NF340 ameliorates inflammation in human fibroblast‐like synoviocytes: An implication in rheumatoid arthritis

P2Y11 receptor antagonist NF340 ameliorates inflammation in human fibroblast‐like synoviocytes: An implication in rheumatoid arthritis

Mitochondria Synergize With P2 Receptors to Regulate Human T Cell Function

Exogenous NAD+ Stimulates MUC2 Expression in LS 174T Goblet Cells via the PLC-Delta/PTGES/PKC-Delta/ERK/CREB Signaling Pathway

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