ArticleProceedings of the National Academy of Sciences of the United States of America2012
β-Arrestin-2 mediates the proinflammatory effects of proteinase-activated receptor-2 in the airway.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2012. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 52 papers.
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The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
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Who cites it
52 citing papers in PubMed, 78 citations in OpenAlex.
- Targeting PAR-2 with a negative allosteric modulator increases tumor antigen presentation and potentiates anti-PD-1 immunotherapy.Journal for immunotherapy of cancer · 2026Article
- Protease-Activated Receptor-2 Promotes Metastasis: An Emerging Therapeutic Target.Molecular cancer research : MCR · 2026Review
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- Protease-Activated Receptor 2 in inflammatory skin disease: current evidence and future perspectives.Frontiers in immunology · 2024Review
- β-Arrestin-biased proteinase-activated receptor-2 antagonist C781 limits allergen-induced airway hyperresponsiveness and inflammation.British journal of pharmacology · 2023Article
- Protease-activated receptors in health and disease.Physiological reviews · 2023Review
- Sensing of protease activity as a triggering mechanism of Th2 cell immunity and allergic disease.Frontiers in allergy · 2023Review
- Proteinase-activated receptor-2 antagonist C391 inhibits Alternaria-induced airway epithelial signalling and asthma indicators in acute exposure mouse models.British journal of pharmacology · 2022Article
- TNF-α impairs EP4 signaling through the association of TRAF2-GRK2 in primary fibroblast-like synoviocytes.Acta pharmacologica Sinica · 2022Article
- MiR-365-3p is a negative regulator in IL-17-mediated asthmatic inflammation.Frontiers in immunology · 2022Article
- βLung · 2021Article
- RGS proteins, GRKs, and beta-arrestins modulate G protein-mediated signaling pathways in asthma.Pharmacology & therapeutics · 2021Review
- Can GPCRs Be Targeted to Control Inflammation in Asthma?Advances in experimental medicine and biology · 2021Article
- Shedding Light on the Role of Neurotransmitters in the Microenvironment of Pancreatic Cancer.Frontiers in cell and developmental biology · 2021Review
- The PAR2 inhibitor I-287 selectively targets GαCommunications biology · 2020Article
- Novel airway smooth muscle-mast cell interactions and a role for the TRPV4-ATP axis in non-atopic asthma.The European respiratory journal · 2020Article
- Discovery of Novel Nonpeptidic PAR2 Ligands.ACS medicinal chemistry letters · 2020Article
- Article
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Authors and funding
11 authors at 6 institutions in 3 countries.
Funding
Abstract
Proteinase-Activated receptor-2 (PAR(2)), a G-protein-coupled Receptor, activated by serine proteinases, is reported to have both protective and proinflammatory effects in the airway. Given these opposing actions, both inhibitors and activators of PAR(2) have been proposed for treating asthma. PAR(2) can signal through two independent pathways: a β-arrestin-dependent one that promotes leukocyte migration, and a G-protein/Ca(2+) one that is required for prostaglandin E(2) (PGE(2)) production and bronchiolar smooth muscle relaxation. We hypothesized that the proinflammatory responses to PAR(2) activation are mediated by β-arrestins, whereas the protective effects are not. Using a mouse ovalbumin model for PAR(2)-modulated airway inflammation, we observed decreased leukocyte recruitment, cytokine production, and mucin production in β-arrestin-2(-/-) mice. In contrast, PAR(2)-mediated PGE(2) production, smooth muscle relaxation, and decreased baseline airway resistance (measures of putative PAR(2) "protective" effects) were independent of β-arrestin-2. Flow cytometry and cytospins reveal that lung eosinophil and CD4 T-cell infiltration, and production of IL-4, IL-6, IL-13, and TNFα, were enhanced in wild-type but not β-arrestin-2(-/-) mice. Using the forced oscillation technique to measure airway resistance reveals that PAR(2) activation protects against airway hyperresponsiveness by an unknown mechanism, possibly involving smooth muscle relaxation. Our data suggest that the PAR(2)-enhanced inflammatory process is β-arrestin-2 dependent, whereas the protective anticonstrictor effect of bronchial epithelial PAR(2) may be β-arrestin independent.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.