Human β Defensin-3 Increases CD86 Expression on Monocytes by Activating the ATP-Gated Channel P2X7

Lioi, Anthony B.; Ferrari, Brian; Dubyak, George R.; Weinberg, Aaron; Sieg, Scott F.

doi:10.4049/jimmunol.1401319

Cited by 20 publications

(18 citation statements)

References 48 publications

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“…P2X7R signalling induces inflammation leading to differentiation of Th17 lymphocytes, which are involved in the pathogenesis and potential treatment of psoriasis ( Killeen et al, 2013 ). P2X7R play a role in shaping the inflammatory microenvironment in psoriasis ( Lioi et al, 2015 ). Strong P2X7R expression is confined to the basal layer cell membrane, while P2Y 1 R were expressed all through the psoriatic epidermis.…”

Section: Skin Diseasesmentioning

confidence: 99%

Purinergic Signalling: Therapeutic Developments

2017

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Purinergic signalling, i.e., the role of nucleotides as extracellular signalling molecules, was proposed in 1972. However, this concept was not well accepted until the early 1990’s when receptor subtypes for purines and pyrimidines were cloned and characterised, which includes four subtypes of the P1 (adenosine) receptor, seven subtypes of P2X ion channel receptors and 8 subtypes of the P2Y G protein-coupled receptor. Early studies were largely concerned with the physiology, pharmacology and biochemistry of purinergic signalling. More recently, the focus has been on the pathophysiology and therapeutic potential. There was early recognition of the use of P1 receptor agonists for the treatment of supraventricular tachycardia and A2A receptor antagonists are promising for the treatment of Parkinson’s disease. Clopidogrel, a P2Y12 antagonist, is widely used for the treatment of thrombosis and stroke, blocking P2Y12 receptor-mediated platelet aggregation. Diquafosol, a long acting P2Y2 receptor agonist, is being used for the treatment of dry eye. P2X3 receptor antagonists have been developed that are orally bioavailable and stable in vivo and are currently in clinical trials for the treatment of chronic cough, bladder incontinence, visceral pain and hypertension. Antagonists to P2X7 receptors are being investigated for the treatment of inflammatory disorders, including neurodegenerative diseases. Other investigations are in progress for the use of purinergic agents for the treatment of osteoporosis, myocardial infarction, irritable bowel syndrome, epilepsy, atherosclerosis, depression, autism, diabetes, and cancer.

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Section: Skin Diseasesmentioning

confidence: 99%

Purinergic Signalling: Therapeutic Developments

2017

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“…LPS, on the other hand, acts primarily via TLR‐4 which further transduces through MyD88 or TRIF (which does not require PI(4,5)P 2 ) to activate NF‐κB, implying that the role of PI(4,5)P 2 does not appear critical and, hence, are not affected by wortmannin, neomycin or staurosporine. PI(4,5)P 2 binding of HBD‐3 might also explain IL‐1β induction and co‐stimulatory marker expression via ATP‐gated channel P2X 7 which is directly regulated by PI(4,5)P 2 …”

Section: Discussionmentioning

confidence: 99%

“…In addition, HBD‐3 induces proinflammatory cytokine release in monocytes, macrophages, and keratinocytes as well as promotes iDC and monocyte maturation by activating NF‐κB, possibly through CCR2/6‐PLC‐dependent and/or TLR‐1/2‐dependent pathways . HBD‐3 can also induce co‐stimulatory marker expression via activation of ATP‐gated P2X 7 channel . In contrast, it was later demonstrated that the HBD‐3‐induced NF‐κB activation was not inhibited by a G‐protein inhibitor pertussis toxin, a MyD88 inhibitor or TLR‐1 or TRIF inhibitor, suggesting a G‐coupled protein‐ and TLR‐independent mechanism .…”

Section: Introductionmentioning

confidence: 99%

“…6,23,26,27 HBD-3 can also induce co-stimulatory marker expression via activation of ATP-gated P2X 7 channel. 28,29 In contrast, it was later demonstrated that the HBD-3-induced NF-jB activation was not inhibited by a G-protein inhibitor pertussis toxin, a MyD88 inhibitor or TLR-1 or TRIF inhibitor, suggesting a G-coupled protein-and TLR-independent mechanism. 30 Alternatively, the authors suggested NF-jB was noncanonically activated through PI3K-Akt signaling, 30 although the detailed mechanism of PI3K-Akt stimulation by HBD-3 remained unclear.…”

Section: Introductionmentioning

confidence: 99%

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Importance of phosphoinositide binding by human β‐defensin 3 for Akt‐dependent cytokine induction

2017

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Host defense peptides (HDPs) are well-characterized for their antimicrobial activities but also variously display potent immunomodulatory effects. Human β-defensin 3 (HBD-3) belongs to a well-known HDP family known as defensins and is able to induce leukocyte chemotactic recruitment, leukocyte activation/maturation, proinflammatory cytokine release, and co-stimulatory marker expression. HBD-3-stimulated cytokine induction is NF-κB-dependent and was initially suggested to act via G protein-coupled C-C chemokine receptor phospholipase C (PLC) and/or Toll-like receptor signaling. Subsequent pharmacological inhibition, however, revealed that NF-κB activation by HBD-3 is receptor-independent and instead involves the phosphoinositide 3-kinase (PI3K)-protein kinase B (Akt) pathway, the mechanism of which remains undetermined. Recently, we have shown that HBD-3 can enter mammalian cells and bind to inner membrane phosphoinositide 4,5-bisphosphate [PI(4,5)P], an important second lipid messenger of PLC and PI3K-Akt pathways. In this study, we report that the interaction of HBD-3 with PI(4,5)P is important for PI3K-Akt-NF-κΒ-mediated induction of tumor necrosis factor and interleukin-6. These data provide insights into the mechanism of immunomodulation by HBD-3, and more generally, highlight the complex multifaceted signaling roles of HDPs in innate defense. Furthermore, it is suggested that the proposed mode of action may be conserved in other HDPs.

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“…Research studies suggested that intrathecal gp120 may lead to an activation of NF-κB within the spinal cord in exaggerated pain states (Ledeboer et al, 2005), and gp120 has been shown to promote tissue and cell injury by inducing NF-κB activation (Kapasi et al, 2006). Previous researchers have found that P2X 7 receptors play a vital role in regulating the function of microglia, and can be activated by adenosine 5'-triphosphate (ATP), thus releasing inflammatory cytokines to mediate chronic inflammatory responses in neurons, ultimately resulting in neurotoxicity (Feng et al, 2015;Lioi et al, 2015). The P2X 7 receptor, which is involved in inflammatory and immune responses and is closely associated with neurodegenerative diseases, may represent a new target for the prevention and treatment of ADC.…”

Section: Introductionmentioning

confidence: 99%

Protective effects of naringin against gp120-induced injury mediated by P2X7 receptors in BV2 microglial cells

Chen

Qin

et al. 2016

Genet. Mol. Res.

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ABSTRACT. This study was aimed at exploring the effects of P2X 7 receptors on gp120-induced injury and naringin's protective effects against gp120-induced injury in BV2 microglia. BV2 microglia injury model was established by gp120 treatment and MTS assay was used to verify whether naringin has a cell-protective effect against gp120-induced injury. Changes in P2X 7 receptor expression were assayed using RT-PCR, qPCR, and western blot. Results showed that the ODs of the Ctrl, gp120, gp120+naringin, and gp120+BBG groups were 0.91 ± 0.10, 0.71 ± 0.09, 0.83 ± 0.10, and 0.83 ± 0.10, respectively. Compared to the control group, the gp120 group showed a significantly decreased cell survival rate. Cell survival rates of the gp120+naringin group increased significantly compared to those of the gp120 group, while no difference was observed when compared to the gp120+BBG group. The relative P2X 7 mRNA expression levels in the Ctrl, gp120, gp120+naringin, and gp120+BBG groups were 0.73 ± 0.06, 1.05 ± 0.06, 0.78 ± 0.05, and 0.81 ± 0.04, respectively. The corresponding P2X 7 protein expression levels were 0.46 ± 0.04, 0.79 ± 0.04, 0.38 ± 0.07, and 0.42 ± 0.06. P2X 7 mRNA and protein expression in the gp120 group increased significantly compared to those in the control group, and declined in the gp120+naringin group compared to those in the gp120 group. Therefore, P2X 7 receptors might be involved in gp120-induced injury in BV2 microglia, and naringin might play a protective role by inhibiting the up-regulated expression of P2X 7 receptors.

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Human β Defensin-3 Increases CD86 Expression on Monocytes by Activating the ATP-Gated Channel P2X7

Cited by 20 publications

References 48 publications

Purinergic Signalling: Therapeutic Developments

Purinergic Signalling: Therapeutic Developments

Importance of phosphoinositide binding by human β‐defensin 3 for Akt‐dependent cytokine induction

Protective effects of naringin against gp120-induced injury mediated by P2X7 receptors in BV2 microglial cells

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