Protease-activated Receptor-2 (PAR2) in the Airways

Cocks, T. M.; Moffatt, James D.

doi:10.1006/pupt.2001.0285

Cited by 110 publications

(119 citation statements)

References 36 publications

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“…Ser, His, and Asp, that, in its three-dimensional spatial arrangement, constitutes the active site of this family of proteolytic enzymes (reviewed in Refs. 7,12,13). Indeed, in addition to proteases generated at the inflammatory site that are known to activate PAR 2 (e.g.…”

Section: Discussionmentioning

confidence: 99%

“…11,12). Importantly, the presence of PARs on epithelia, endothelia, monocytes, and macrophages (reviewed in Ref.…”

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

confidence: 99%

“…7) suggests a possible role for PARs in the innate immune defense and immune surveillance (reviewed in Refs. 4,[11][12][13]. However, innate immunity has largely been attributed to the capacity of "pattern-recognition receptors" (PRRs) to respond to conserved "pathogen-associated molecular patterns" (PAMPs) (reviewed in Ref.…”

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

134

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: Discussionmentioning

confidence: 99%

“…11,12). Importantly, the presence of PARs on epithelia, endothelia, monocytes, and macrophages (reviewed in Ref.…”

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%

See 1 more Smart Citation

Analysis of Proteinase-activated Receptor 2 and TLR4 Signal Transduction

Rallabhandi

Nhu

Toshchakov

et al. 2008

Journal of Biological Chemistry

134

149

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“…However, there is controversy about whether PAR2 agonists protect or promote airway inflammation. In support of a protective role are observations that PAR2 agonists induce an eicosanoid-dependent bronchodilation in rats, mice, and guinea pigs (8,12,13), and that intranasal administration of a PAR2 agonist in mice reduces the infiltration of neutrophils into bronchoalveolar lavage (BAL) after treatment with LPS (11). PAR2 agonists also relax the guinea pig trachea and human bronchi by releasing eicosanoids and NO from the epithelium (9,10).…”

Section: Protease-activated Receptor 2 Mediates Eosinophil Infiltratimentioning

confidence: 97%

“…Trypsin is the most potent PAR2 agonist, and trypsin-like enzymes have been detected in airway epithelial cells (8,11) and in airway secretions (11,45). The purification and characterization of these enzymes is required to ascertain their effectiveness as PAR2 agonists.…”

Section: Tryptase and Trypsin May Activate Par2 In The Inflamed Airwaymentioning

confidence: 99%

Protease-Activated Receptor 2 Mediates Eosinophil Infiltration and Hyperreactivity in Allergic Inflammation of the Airway

Schmidlin

Amadesi

Dabbagh³

et al. 2002

The Journal of Immunology

305

260

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Trypsin and mast cell tryptase can signal to epithelial cells, myocytes, and nerve fibers of the respiratory tract by cleaving proteinase-activated receptor 2 (PAR2). Since tryptase inhibitors are under development to treat asthma, a precise understanding of the contribution of PAR2 to airway inflammation is required. We examined the role of PAR2 in allergic inflammation of the airway by comparing OVA-sensitized and -challenged mice lacking or overexpressing PAR2. In wild-type mice, immunoreactive PAR2 was detected in airway epithelial cells and myocytes, and intranasal administration of a PAR2 agonist stimulated macrophage infiltration into bronchoalveolar lavage fluid. OVA challenge of immunized wild-type mice stimulated infiltration of leukocytes into bronchoalveolar lavage and induced airway hyperreactivity to inhaled methacholine. Compared with wild-type animals, eosinophil infiltration was inhibited by 73% in mice lacking PAR2 and increased by 88% in mice overexpressing PAR2. Similarly, compared with wild-type animals, airway hyperreactivity to inhaled methacholine (40 μg/ml) was diminished 38% in mice lacking PAR2 and increased by 52% in mice overexpressing PAR2. PAR2 deletion also reduced IgE levels to OVA sensitization by 4-fold compared with those of wild-type animals. Thus, PAR2 contributes to the development of immunity and to allergic inflammation of the airway. Our results support the proposal that tryptase inhibitors and PAR2 antagonists may be useful therapies for inflammatory airway disease.

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