Protease-Activated Receptor-2 Activation

Holzhausen, Marinella; Spolidorio, Luís Carlos; Ellen, Richard P.; Jobin, Marie-Claude; Steinhoff, Martin; Andrade‐Gordon, Patricia; Vergnolle, Nathalie

doi:10.2353/ajpath.2006.050658

Cited by 101 publications

(39 citation statements)

References 43 publications

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“…Consequently, several microbes evade PAR 2 -mediated immune surveillance by directly disabling the receptor. For example, proteases from Pseudomonas aeruginosa (21) or Treponema denticola (15) have been reported to inactivate PAR 2 and thereby alter its function.…”

Section: Ap-inducible Nf-b Reporter Activation That Was Protein Synthmentioning

confidence: 99%

“…Specifically, PAR 2 has been associated with the inflammatory response to infection and microbial proteases and, in this context, may also act as a PRR. In mice, PAR 2 activation plays a pivotal role in the pathogenesis of periodontitis caused by Porphyromonas gingivalis (15) and in the development of infectious colitis induced by Citrobacter rodentium (16). Exposure of PAR 2 to proteases derived from P. gingivalis (17) or Serratia marcescens (18) induces expression of the antimicrobial peptide ␤-defensin 2 (17), pro-inflammatory cytokines and chemokines, e.g.…”

Section: Ap-inducible Nf-b Reporter Activation That Was Protein Synthmentioning

confidence: 99%

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Analysis of Proteinase-activated Receptor 2 and TLR4 Signal Transduction

Rallabhandi

Nhu

Toshchakov

et al. 2008

Journal of Biological Chemistry

135

149

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Proteinase-activated receptor 2 (PAR 2 ), a seven-transmembrane G protein-coupled receptor, is activated at inflammatory sites by proteolytic cleavage of its extracellular N terminus by trypsin-like enzymes, exposing a tethered, receptor-activating ligand. Synthetic agonist peptides (AP) that share the tethered ligand sequence also activate PAR 2 , often measured by Ca 2؉ release. PAR 2 contributes to inflammation through activation of NF-B-regulated genes; however, the mechanism by which this occurs is unknown. Overexpression of human PAR 2 in HEK293T cells resulted in concentration-dependent, PAR 2 AP-inducible NF-B reporter activation that was protein synthesis-independent, yet blocked by inhibitors that uncouple G i proteins or sequester intracellular Ca 2؉ . Because previous studies described synergistic PAR 2 -and TLR4-mediated cytokine production, we hypothesized that PAR 2 and TLR4 might interact at the level of signaling. In the absence of TLR4, PAR 2 -induced NF-B activity was inhibited by dominant negative (DN)-TRIF or DN-TRAM constructs, but not by DN-MyD88, findings confirmed using cell-permeable, adapter-specific BB loop blocking peptides. Co-expression of TLR4/MD-2/CD14 with PAR 2 in HEK293T cells led to a synergistic increase in AP-induced NF-B signaling that was MyD88-dependent and required a functional TLR4, despite the fact that AP exhibited no TLR4 agonist activity. Co-immunoprecipitation of PAR 2 and TLR4 revealed a physical association that was AP-dependent. The response to AP or lipopolysaccharide was significantly diminished in TLR4 ؊/؊ and PAR 2 ؊/؊ macrophages, respectively, and SW620 colonic epithelial cells exhibited synergistic responses to co-stimulation with AP and lipopolysaccharide. Our data suggest a unique interaction between two distinct innate immune response receptors and support a novel paradigm of receptor cooperativity in inflammatory responses.

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Section: Ap-inducible Nf-b Reporter Activation That Was Protein Synthmentioning

confidence: 99%

Section: Ap-inducible Nf-b Reporter Activation That Was Protein Synthmentioning

confidence: 99%

Analysis of Proteinase-activated Receptor 2 and TLR4 Signal Transduction

Rallabhandi

Nhu

Toshchakov

et al. 2008

Journal of Biological Chemistry

135

149

View full text Add to dashboard Cite

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“…Although proteases of the coagulation cascade constitute important candidates to activate PAR-1, their relative contribution to PAR activation compared with other proteases of the immune response is difficult to apprehend. Trypsins, tryptase, and cathepsins, which are released by inflammatory cells, or even pathogen proteases [26] are also able to signal through PAR activation. So the proteases of the immune response may activate PAR-1 in allogeneic CD8 ?…”

Section: Discussionmentioning

confidence: 99%

Proteinase-activated receptor-1 mediates allogeneic CD8+ T cell-induced apoptosis of vascular endothelial cells

Zhang

Zou

et al. 2008

Med Oncol

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Vascular endothelial-cells injury plays a pivotal role in the pathogenesis of graft-versus-host disease (GVHD) and transplant-associated endothelial injury syndrome. Vascular endothelial cells are an exposed target tissue for immune-mediated injury during GVHD. Early endothelial injury syndromes share common features with acute GVHD. Chronic GVHD leads to a rarefaction of microvessels caused by the infiltration of alloreactive cytotoxic T lymphocytes. In this context, allogeneic reactive cytotoxic T cell may contribute to apoptosis of vascular endothelial cells. The involvement of proteinase-activated receptor (PAR-1) in regulation of apoptosis has been recently recognized in many cell types. We hypothesized that apoptosis of vascular endothelial cells induced by allogeneic cytotoxic T cell are mediated via the PAR-1. Allogeneic CD8(+) T cell, PAR-1 agonist peptide (SFLLRN) induced apoptosis of human umbilical vein endothelial cells (HUVECs) and human dermal microvascular endothelial cells (HDMECs) as assessed by AnnexinV-FITC labeling. To ascertain the mechanism of endothelial apoptosis, we determined that allogeneic CD8(+) T cell, SFLLRN enhanced cleavage of caspase-3 and led to p38MAPK activation as assessed by Western blot. The effects of allogeneic CD8(+) T cell and SFLLRN on apoptosis of vascular endothelial cells were largely prevented by a cleavage-blocking anti-human PAR-1-antibody (ATAP2) and a specific inhibitor of p38MAPK. In concert, these observations provide strong evidence that allogeneic CD8(+) T cell induces apoptosis of human vascular endothelial cells through PAR-1-dependent modulation of intrinsic apoptotic pathway via alterations of p38MAPK and caspase-3.

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“…Importantly, P. aeruginosa secrets elastase B (EPa) which potentially silences the role of PAR2 in the respiratory tract and alters the host’s innate defense mechanisms and respiratory tract functions, thus EPa by PAR2 signaling contributes a significant role in the pathogenesis of a disease like cystic fibrosis [66] . Other microorganisms such as Serratia marcescens (gram-negative enteric bacterium), and Porphyromonas gingivalis and Aggregatibacter actinomycetemcomitans (gram-negative bacterium causes periodontitis), activate PAR2 and induce proinflammatory cytokines secretion [67–69] and stimulate inflammatory responses in vitro and in vivo [70, 71] .…”

Section: Activation Of Pars and Role Of Pathogen-derived Proteases Inmentioning

confidence: 99%

Role of Protease-Activated Receptors 2 (PAR2) in Ocular Infections and Inflammation

Tripathi

Alizadeh

2014

Receptor Clin Invest

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Protease-activated receptors (PARs) belong to a unique family of G protein-coupled receptors (GPCRs) that are cleaved at an activation site within the N-terminal exodomain by a variety of proteinases, essentially of the serine (Ser) proteinase family. After cleavage, the new N-terminal sequence functions as a tethered ligand, which binds intramolecularly to activate the receptor and initiate signaling. Cell signals induced through the activation of PARs appear to play a significant role in innate and adoptive immune responses of the cornea, which is constantly exposed to proteinases under physiological or pathophysiological conditions. Activation of PARs interferes with all aspects of the corneal physiology such as barrier function, transports, innate and adoptive immune responses, and functions of corneal nerves. It is not known whether the proteinase released from the microorganism can activate PARs and triggers the inflammatory responses. The role of PAR2 expressed by the corneal epithelial cells and activation by serine protease released from microorganism is discussed here. Recent evidences suggest that activation of PAR2, by the serine proteinases, play an important role in innate and inflammatory responses of the corneal infection.

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Protease-Activated Receptor-2 Activation

Cited by 101 publications

References 43 publications

Analysis of Proteinase-activated Receptor 2 and TLR4 Signal Transduction

Analysis of Proteinase-activated Receptor 2 and TLR4 Signal Transduction

Proteinase-activated receptor-1 mediates allogeneic CD8+ T cell-induced apoptosis of vascular endothelial cells

Role of Protease-Activated Receptors 2 (PAR2) in Ocular Infections and Inflammation

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