Co-existence of two types of [Ca2+]i-inducing protease-activated receptors (PAR-1 and PAR-2) in rat astrocytes and C6 glioma cells

Ubl, Joachim J.; Vöhringer, Christian; Reiser, Georg

doi:10.1016/s0306-4522(97)00686-6

Cited by 98 publications

(87 citation statements)

References 43 publications

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“…55). However, previous studies that investigated PAR-1 on astrocytes focused on the effect of PAR-1 activation on calcium signaling and morphology (11,14,56) and signaling through mitogen-activated protein kinase (57), but many of the downstream effects on gene expression remain largely unknown. This is the first report to show that PAR-1-mediated activation of astrocytes results in the induction of inflammatory mediators.…”

Section: Discussionmentioning

confidence: 99%

“…Since PAR-1 has been shown to be expressed by astrocytes (11), and astrocytes are important modulators of brain inflammation (46), we determined whether astrocytes could be immune-activated by thrombin and if this effect was dependent on PAR-1 specifically by also testing the selective PAR-1-activating peptide (TF). The reverse peptide, RL, was used as a control for TF, and cells were treated with the selective PAR-4-activating AY peptide B (47) to ensure that thrombin-induced effects were not PAR-4 mediated.…”

Section: Stimulation Of Human Astrocytic U373 Cells and Primary Astromentioning

confidence: 99%

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Up-Regulation of Proteinase-Activated Receptor 1 Expression in Astrocytes During HIV Encephalitis

Boven¹,

Vergnolle²,

Henry³

et al. 2003

The Journal of Immunology

112

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Proteinase-activated receptor 1 (PAR-1) is a G protein-coupled receptor that is activated by thrombin and is implicated in the pathogenesis of inflammation. Although PAR-1 is expressed on immunocompetent cells within the brain such as astrocytes, little is known about its role in the pathogenesis of inflammatory brain diseases. Herein, we investigated PAR-1 regulation of brain inflammation by stimulating human astrocytic cells with thrombin or the selective PAR-1-activating peptide. Activated cells expressed significantly increased levels of IL-1β, inducible NO synthase, and PAR-1 mRNA. Moreover, supernatants of these same cells were neurotoxic, which was inhibited by an N-methyl-d-aspartate receptor antagonist. Striatal implantation of the PAR-1-activating peptide significantly induced brain inflammation and neurobehavioral deficits in mice compared with mice implanted with the control peptide or saline. Since HIV-related neurological disease is predicated on brain inflammation and neuronal injury, the expression of PAR-1 in HIV encephalitis (HIVE) was investigated. Immunohistochemical analysis revealed that PAR-1 and (pro)-thrombin protein expression was low in control brains, but intense immunoreactivity was observed on astrocytes in HIVE brains. Similarly, PAR-1 and thrombin mRNA levels were significantly increased in HIVE brains compared with control and multiple sclerosis brains. These data indicated that activation and up-regulation of PAR-1 probably contribute to brain inflammation and neuronal damage during HIV-1 infection, thus providing new therapeutic targets for the treatment of HIV-related neurodegeneration.

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Section: Discussionmentioning

confidence: 99%

Section: Stimulation Of Human Astrocytic U373 Cells and Primary Astromentioning

confidence: 99%

Up-Regulation of Proteinase-Activated Receptor 1 Expression in Astrocytes During HIV Encephalitis

Boven¹,

Vergnolle²,

Henry³

et al. 2003

The Journal of Immunology

112

View full text Add to dashboard Cite

show abstract

“…The recent finding of a thrombin-generating system in the brain and the presence of PAR-1 in neurons and glia suggest that PAR-1 may have functions in addition to revascularization (Ubl et al 1998). PAR-2 activation has been related to release of proteinases in inflammatory and allergic conditions, vasodilatation of cerebral arteries, release of prostaglandins, and regulation of cytokine production in enterocytes (Wakita et al 1997;Sobey et al 1999).…”

Section: Discussionmentioning

confidence: 99%

Presence of functionally active protease‐activated receptors 1 and 2 in myenteric glia

Garrido

Segura

Zhang³

et al. 2002

Journal of Neurochemistry

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“…In astrocytes and C6 glioma cells, thrombin-induced Ca 2ϩ mobilization is mimicked by TRAP and blocked by cathepsin G (41,42). Activation of platelets could be achieved by both thrombin and TRAP (43).…”

Section: Fig 5 Thrombin Activates Nf-bmentioning

confidence: 99%

Thrombin Induces NO Release from Cultured Rat Microglia via Protein Kinase C, Mitogen-activated Protein Kinase, and NF-κB

Ryu

Pyo

Jou

et al. 2000

Journal of Biological Chemistry

152

140

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Microglia, brain resident macrophages, become activated in brains injured due to trauma, ischemia, or neurodegenerative diseases. In this study, we found that thrombin treatment of microglia induced NO release/ inducible nitric-oxide synthase expression, a prominent marker of activation. The effect of thrombin on NO release increased dose-dependently within the range of 5-20 units/ml. In immunoblot analyses, inducible nitricoxide synthase expression was detected within 9 h after thrombin treatment. This effect of thrombin was significantly reduced by protein kinase C inhibitors, such as Go6976, bisindolylmaleimide, and Ro31-8220. Within 15 min, thrombin activated three subtypes of mitogen-activated protein kinases: extracellular signal-regulated kinase, p38, and c-Jun N-terminal kinase/stress-activated protein kinase. Inhibition of the extracellular signalregulated kinase pathway and p38 reduced the NO release of thrombin-treated microglia. Thrombin also activated nuclear factor B (NF-B) within 5 min, and N-acetyl cysteine, an inhibitor of NF-B, reduced NO release. However, thrombin receptor agonist peptide (an agonist of protease activated receptor-1 (PAR-1)), could not mimic the effect of thrombin, and cathepsin G, a PAR-1 inhibitor, did not reduce the effect of thrombin. These results suggest that thrombin can activate microglia via protein kinase C, mitogen-activated protein kinases, and NF-B but that this occurs independently of PAR-1.

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Co-existence of two types of [Ca2+]i-inducing protease-activated receptors (PAR-1 and PAR-2) in rat astrocytes and C6 glioma cells

Cited by 98 publications

References 43 publications

Up-Regulation of Proteinase-Activated Receptor 1 Expression in Astrocytes During HIV Encephalitis

Up-Regulation of Proteinase-Activated Receptor 1 Expression in Astrocytes During HIV Encephalitis

Presence of functionally active protease‐activated receptors 1 and 2 in myenteric glia

Thrombin Induces NO Release from Cultured Rat Microglia via Protein Kinase C, Mitogen-activated Protein Kinase, and NF-κB

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