Protease-activated receptor-2-mediated inhibition of ion transport in human bronchial epithelial cells

Danahay, Henry; Withey, Louise; Poll, Chris; Graaf, Stan F.J. van de; Bridges, Robert J.

doi:10.1152/ajpcell.2001.280.6.c1455

Cited by 47 publications

(44 citation statements)

References 26 publications

(47 reference statements)

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“…Similarly, PAR-2 regulates electrolyte transport in the airway epithelium, although there is no evidence for PAR-1 regulation of ion transport in the respiratory system (37,38). PAR-2 activators, when added to the basolateral, but not apical, surface of airway epithelial cells, regulate Na + absorption and Cl -secretion in a cytosolic Ca 2+ -dependent manner (37).…”

Section: Modulation Of Smooth Muscle Motility and Ion Transport By Prmentioning

confidence: 99%

Physiology and Pathophysiology of Proteinase-Activated Receptors (PARs): PARs in the Respiratory System: Cellular Signaling and Physiological/Pathological Roles

Kawabata

Kawao

2005

J Pharmacol Sci

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Abstract. Proteinase-activated receptors (PARs), a family of G protein-coupled receptors, are widely distributed in the mammalian body, playing a variety of physiological / pathophysiological roles. In the respiratory systems, PARs, particularly PAR-2 and PAR-1, are expressed in the epithelial and smooth muscle cells. In addition to the G q/ 11 -mediated activation of the phospholipase Cb pathway, epithelial PAR activation causes prompt and / or delayed prostanoid formation, leading to airway smooth muscle relaxation and / or modulation of an inflammatory process. PAR-2 present in the epithelium and smooth muscle is considered primarily pro-inflammatory in the respiratory system, although PAR-2 may also be anti-inflammatory under certain conditions. In the lung epithelial cells, PAR-2 can also be activated by exogenous proteinases including house dust mite allergens, in addition to various possible endogenous agonist proteinases. Clinical evidence also suggests possible involvement of PARs, particularly PAR-2, in respiratory diseases. PARs thus appear to play critical roles in the respiratory systems, and the agonists/ antagonists for PARs may serve as the novel therapeutic strategy for treatment of certain respiratory diseases including asthma.

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Section: Modulation Of Smooth Muscle Motility and Ion Transport By Prmentioning

confidence: 99%

Physiology and Pathophysiology of Proteinase-Activated Receptors (PARs): PARs in the Respiratory System: Cellular Signaling and Physiological/Pathological Roles

Kawabata

Kawao

2005

J Pharmacol Sci

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“…Second, Chokki and coworkers (55) showed that human airway trypsin-like protease, but not a PAR-2-activating peptide, induced MUC2 and MUC5AC gene expression in NCI-H292 cells. Finally, PAR-2 expression was restricted to the basolateral surface of airway epithelial cells (56), which would render it inaccessible to NE released by luminal neutrophils on the apical side of respiratory mucosa. Our recent unpublished data showed that while trypsin also induced MUC1 transcription, its activity was less than 10% of that generated by NE (I. Kuwahara, unpublished data).…”

Section: Discussionmentioning

confidence: 99%

The Signaling Pathway Involved in Neutrophil Elastase–Stimulated MUC1 Transcription

Kuwahara

Lillehoj²,

Koga³

et al. 2007

Am J Respir Cell Mol Biol

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We previously reported that neutrophil elastase (NE) stimulated MUC1 gene expression in A549 lung epithelial cells through binding of Sp1 to the MUC1 promoter element. The current study was undertaken to elucidate the complete signaling pathway leading to Sp1 activation. Using a combination of pharmacologic inhibitors, dominantnegative mutant, RNA interference, and soluble receptor blocking techniques, we identified a protein kinase Cd (PKCd) / dual oxidase 1 (Duox1) / reactive oxygen species (ROS) / TNF-a-converting enzyme (TACE) / TNF-a / TNF receptor (TNFR)1 / extracellular signal-regulated kinase (ERK)1/2 / Sp1 pathway as responsible for NE-activated MUC1 transcription. This cascade was identical up to the point of TACE with the signaling pathway previously reported for NE-stimulated MUC5AC production. However, unlike the MUC5AC pathway, TNF-a, TNFR1, ERK1/2, and Sp1 were unique components of the MUC1 pathway. Given the anti-inflammatory role of MUC1 during airway bacterial infection, up-regulation of MUC1 by inflammatory mediators such as NE and TNF-a suggests a crucial role for MUC1 in the control of excessive inflammation during airway bacterial infection.Keywords: neutrophil elastase; MUC1; signaling; airway MUC1 (MUC1 in human and Muc1 in nonhuman species) is a transmembrane mucin-like glycoprotein expressed on the surface of epithelial cells lining various mucosal surfaces, including the respiratory tract (1-3). We recently showed that mice deficient in Muc1 expression exhibited both enhanced airway inflammation and bacterial clearance during Pseudomonas aeruginosa (PA) airway infection (4), suggesting an anti-inflammatory role for Muc1 and the importance of Muc1 levels during airway bacterial infection. The anti-inflammatory activity of MUC1/Muc1 after treatment with bacterial products also was demonstrated in various in vitro studies (4). How the levels of MUC1/Muc1 are regulated during airway bacterial infection is unknown, but recent evidence indicates the involvement of neutrophil elastase (NE) (5).NE is present in micromolar concentrations in airway surface liquid of patients with cystic fibrosis and patients with chronic bronchitis (6, 7), and stimulates mucin release and mucin gene expression by cultured airway epithelial cells through the proteolytic activity (8, 9). Using a co-culture system containing hamster neutrophils and tracheal surface epithelial (TSE) cells, we demonstrated that activation of the neutrophils by fMLP or cytochalasin B resulted in the stimulation of mucin release (10), indicating that the concentrations of NE produced by activation of neutrophils are sufficient to release mucins. To date, NE is the most potent mucin secretagogue that has been described (11).In addition to gel-forming mucins such as MUC5AC, NE also induces the expression of the membrane-bound MUC1 and MUC4 mucins (5, 12). Our prior report showed that MUC1 protein synthesis by A549 cells was enhanced after treatment with NE, and this effect was blocked by pretreatment with actinomycin D or cycloheximide (...

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“…PAR2 (F2RL1) is one of the four known PARs and has been shown to play a role in secretion, smooth muscle contractility, neuromodulation, inflammation, fibrosis, angiogenesis and cancer metastasis (Bertog et al, 1999;Cocks et al, 1999;Danahay et al, 2001;Fiorucci et al, 2001;Hoogerwerf et al, 2001;Richard et al, 2001;Vergnolle et al, 2001;Frungieri et al, 2002;Hollenberg, 2002;Milia et al, 2002). We found that increased PAR2 expression enhanced, and reduced expression decreased, growth of RCC cell lines in vitro, suggesting that upregulation of TMSNB and PAR2 following VHL inactivation contributes to RCC tumorigenesis, although, we note that TMSNB and PAR2 were only upregulated in a proportion of primary RCC with VHL inactivation.…”

Section: Discussionmentioning

confidence: 99%

Identification of novel VHL targets that are associated with the development of renal cell carcinoma

et al. 2006

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von Hippel-Lindau (VHL) disease is a dominantly inherited family cancer syndrome characterized by the development of retinal and central nervous system haemangioblastomas, renal cell carcinoma (RCC) and phaeochromocytoma. Specific germline VHL mutations may predispose to haemangioblastomas, RCC and phaeochromocytoma to a varying extent. Although dysregulation of the hypoxia-inducible transcription factor-2 and JunB have been linked to the development of RCC and phaeochromocytoma, respectively, the precise basis for genotype-phenotype correlations in VHL disease have not been defined. To gain insights into the pathogenesis of RCC in VHL disease we compared gene expression microarray profiles in a RCC cell line expressing a Type 1 or Type 2B mutant pVHL (RCC-associated) to those of a Type 2A or 2C mutant (not associated with RCC). We identified 19 differentially expressed novel VHL target genes linked to RCC development. Eight targets were studied in detail by quantitative real-time polymerase chain reaction (three downregulated and five upregulated by wild-type VHL) and for six genes the effect of VHL inactivation was mimicked by hypoxia (but hypoxicinduction of smooth muscle alpha-actin 2 was specific for a RCC cell line). The potential role of four RCCassociated VHL target genes was assessed in vitro. NB thymosin beta (TMSNB) and proteinase-activated receptor 2 (PAR2) (both downregulated by wt pVHL) increased cell growth and motility in a RCC cell line, but aldehyde dehydrogenase (ALDH)1 and ALDH7 had no effect. These findings implicate TMSNB and PAR2 candidate oncogenes in the pathogenesis of VHL-associated RCC.

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Protease-activated receptor-2-mediated inhibition of ion transport in human bronchial epithelial cells

Cited by 47 publications

References 26 publications

Physiology and Pathophysiology of Proteinase-Activated Receptors (PARs): PARs in the Respiratory System: Cellular Signaling and Physiological/Pathological Roles

Physiology and Pathophysiology of Proteinase-Activated Receptors (PARs): PARs in the Respiratory System: Cellular Signaling and Physiological/Pathological Roles

The Signaling Pathway Involved in Neutrophil Elastase–Stimulated MUC1 Transcription

Identification of novel VHL targets that are associated with the development of renal cell carcinoma

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