Protease-activated receptors in human airways: Upregulation of PAR-2 in respiratory epithelium from patients with asthma

Knight, Darryl A.; Lim, Shuang Fang; Scaffidi, Adrian; Roche, Nicolas; Chung, Kian Fan; Stewart, Geoffrey A.; Thompson, Philip J.

doi:10.1067/mai.2001.119025

Cited by 252 publications

(218 citation statements)

References 27 publications

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“…This indicates that PAR-2 was inducible receptor from intracellular storage, and not required de novo synthesis among the PAR family. In support of this, it was reported that the expression of PAR-2 on human endothelial cells was also up-regulated by LPS as well as IL-1␣ and TNF-␣ without an effect on PAR-1 expression (40), and that PAR-2 expression in asthmatic bronchial epithelium was significantly increased in comparison with normal epithelium (41). Recently, the PAR-2-induced activation of keratinocytes was shown to be mediated by the mitogen-activated protein kinase and NF-B pathways (42), which are important for the gene expression of cytokines.…”

Section: Discussionsupporting

confidence: 52%

Activation of Human Oral Epithelial Cells by Neutrophil Proteinase 3 Through Protease-Activated Receptor-2

Uehara¹,

Sugawara²,

Muramoto

et al. 2002

The Journal of Immunology

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Proteinase 3 (PR3), a 29-kDa serine proteinase secreted from activated neutrophils, also exists in a membrane-bound form, and is suggested to actively contribute to inflammatory processes. The present study focused on the mechanism by which PR3 activates human oral epithelial cells. PR3 activated the epithelial cells in culture to produce IL-8 and monocyte chemoattractant protein-1 and to express ICAM-1 in a dose- and time-dependent manner. Incubation of the epithelial cells for 24 h with PR3 resulted in a significant increase in the adhesion to neutrophils, which was reduced to baseline levels in the presence of anti-ICAM-1 mAb. Activation of the epithelial cells by PR3 was inhibited by serine proteinase inhibitors and serum. The epithelial cells strongly express protease-activated receptor (PAR)-1 and PAR-2 mRNA and weakly express PAR-3 mRNA. The expression of PAR-2 on the cell surface was promoted by PR3, and inhibited by cytochalasin B, but not by cycloheximide. PR3 cleaved the peptide corresponding to the N terminus of PAR-2 with exposure of its tethered ligand. Treatment with trypsin, an agonist for PAR-2, and a synthetic PAR-2 agonist peptide induced intracellular Ca2+ mobilization, and rendered cells refractory to subsequent stimulation with PR3 and vice versa. The production of cytokine induced by PR3 and the PAR-2 agonist peptide was completely abolished by a phospholipase C inhibitor. These findings suggest that neutrophil PR3 activates oral epithelial cells through G protein-coupled PAR-2 and actively participates in the process of inflammation such as periodontitis.

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Section: Discussionsupporting

confidence: 52%

Activation of Human Oral Epithelial Cells by Neutrophil Proteinase 3 Through Protease-Activated Receptor-2

Uehara¹,

Sugawara²,

Muramoto

et al. 2002

The Journal of Immunology

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“…Recently, the potential role of PAR-2 in the pathogenesis of inflammation and immune diseases via interaction with serine protease has attracted attention. 14,15,19,[23][24][25] Most studies show that PAR-2 has a proinflammatory effect via PAR-2 agonist experiments, but some reports suggest that PAR-2 can have a protective effect against inflammation. 18,[24][25][26][27][28] Clearly, the role(s) of PAR-2 in inflammation is still not fully understood.…”

Section: Discussionmentioning

confidence: 99%

“…Other recent results include the finding of increased PAR-2 expression in respiratory epithelial cells from patients with asthma. 23 PAR-2 expression and activation can be modulated by differential glycosylation, 38 and activation can also be altered by polymorphic variation. For example, variations in the human PAR-2 in extracellular loop 2 (Phe240/Ser, PAR2F204S) result in significant differential receptor activation by trypsin and PAR agonists.…”

Section: Discussionmentioning

confidence: 99%

“…20 PAR-2 activation on airway epithelial cells causes the release of prostaglandin E2, 18 GM-CSF, eotaxin, 21 and matrix metalloproteinase-9. 22 PAR-2 expression is increased in respiratory epithelial cells of patients with asthma, 23 but the physiological role of PAR-2 in the airways remains unclear. In mice, overexpression of PAR-2 increases eosinophil infiltration and airway hyperresponsiveness whereas absence of PAR-2 expression has the opposite effect.…”

mentioning

confidence: 99%

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A synonymous variation in protease-activated receptor-2 is associated with atopy in Korean children

Lee

Kim

Gee

et al. 2011

Journal of Allergy and Clinical Immunology

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“…These reports show that endogenous or exogenous proteases and PAR agonist peptides can stimulate proinflammatory cytokine release by airway epithelial cells via PARs. There is in vivo evidence that PAR-2 is significantly up-regulated in bronchial epithelium from asthmatic subjects (24). Furthermore, PAR-2 mediates eosinophil infiltration and hyperreactivity in allergic inflammation of the airway (25).…”

mentioning

confidence: 99%

Mold Allergen, Pen c 13, Induces IL-8 Expression in Human Airway Epithelial Cells by Activating Protease-Activated Receptor 1 and 2

Chiu

Perng

et al. 2007

The Journal of Immunology

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Allergenic serine proteases are important in the pathogenesis of asthma. One of these, Pen c 13, is the immunodominant allergen produced by Penicillium citrinum. Many serine proteases induce cytokine expression, but whether Pen c 13 does so in human respiratory epithelial cells is not known. In this study, we investigated whether Pen c 13 caused IL-8 release and activated protease-activated receptors (PARs) in airway epithelial cells. In airway-derived A549 cells and normal human airway epithelial cells, Pen c 13 induced IL-8 release in a dose-dependent manner. Pen c 13 also increased IL-8 release in a time-dependent manner in A549 cells. Pen c 13 cleaved PAR-1 and PAR-2 at their activation sites. Treatment with Pen c 13 induced intracellular Ca2+ mobilization and desensitized the cells to the action of other proteases and PAR-1 and PAR-2 agonists. Moreover, Pen c 13-mediated IL-8 release was significantly decreased in Ca2+-free medium and was abolished by the protease inhibitors, PMSF and 4-(2-aminoethyl) benzenesulfonyl fluoride. Blocking Abs against the cleavage sites of PAR-1 and PAR-2, but not of PAR-4, inhibited Pen c 13-induced IL-8 production, as did inhibition of phospholipase C. Pen c 13 induced IL-8 expression via activation of ERK 1/2, and not of p38 and JNK. In addition, treatment of A549 cells or normal human airway epithelial cells with Pen c 13 increased phosphorylation of ERK 1/2 by a Ca2+-dependent pathway. These finding show that Pen c 13 induces IL-8 release in airway epithelial cells and that this is dependent on PAR-1 and PAR-2 activation and intracellular calcium.

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Protease-activated receptors in human airways: Upregulation of PAR-2 in respiratory epithelium from patients with asthma

Cited by 252 publications

References 27 publications

Activation of Human Oral Epithelial Cells by Neutrophil Proteinase 3 Through Protease-Activated Receptor-2

Activation of Human Oral Epithelial Cells by Neutrophil Proteinase 3 Through Protease-Activated Receptor-2

A synonymous variation in protease-activated receptor-2 is associated with atopy in Korean children

Mold Allergen, Pen c 13, Induces IL-8 Expression in Human Airway Epithelial Cells by Activating Protease-Activated Receptor 1 and 2

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