Involvement of proteinase-activated receptor-2 in mast cell tryptase-induced barrier dysfunction in bovine aortic endothelial cells

Sendo, Toshiaki; Sumimura, Tomoko; Itoh, Yoshinori; Goromaru, Tsuyoshi; Aki, Keisei; Yano, Tomoaki; Oike, Masahiro; Ito, Yushi; Mori, Shuji; Nishibori, Masahiro; Oishi, Ryozo

doi:10.1016/s0898-6568(03)00014-7

Cited by 35 publications

(31 citation statements)

References 40 publications

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“…If PAR-2-mediated production of PGs constitutes a considerable portion of PG synthesis in the colon cancer tissue, the regulation of PAR-2 stimulation would be a new therapeutic target of colon cancer. Nafamostat mesilate was demonstrated to be a very potent inhibitor of human tryptase (11,17). In the present study, nafamostat mesilate concentration-dependently inhibited the tryptaseinduced proliferation of DLD-1 cells.…”

Section: Discussionsupporting

confidence: 57%

“…This finding indicated that DLD-1-proliferating effects of PAR-2 stimulation was mediated by the production of PGs. Nafamostat mesilate was reported to be a very potent inhibitor of human tryptase (10,11,17). Therefore, we determined the antagonizing effects of nafamostat on tryptase-induced proliferation of DLD-1 cells.…”

Section: +mentioning

confidence: 99%

“…Several serine proteinases such as trypsin or trypsin-like proteinase have been suggested to be candidates for PAR-2 agonist proteinase. Among them, mast cell tryptase was reported to be an agonist proteinase for PAR-2 in vascular endothelial cells (10,11). Mast cells are present in mucosa and submucosal tissue of the gastrointestinal tract and there have been many reports suggesting the involvement of mast cells in the growth of tumor tissues through the stimulation of angiogenesis by the active substances released from mast cells (12 -15).…”

Section: Introductionmentioning

confidence: 99%

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Mast Cell Tryptase Stimulates DLD-1 Carcinoma Through Prostaglandin- and MAP Kinase-Dependent Manners

et al. 2005

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Abstract. We found that striptease-positive mast cells were abundant in the invasive front of human colon adenocarcinoma by examining 30 cases. Because tryptase has been suggested to be the agonist proteinase for protease-activated receptor-2 (PAR-2), we investigated the effects of stimulation of PAR-2 by tryptase on the cell signaling and proliferation of DLD-1, a human colon carcinoma cell line. PAR-2 stimulation by tryptase induced the increase in [Ca 2+ ] i , which was desensitized by the prior application of PAR-2 activating peptide (AP). The proliferative responses of DLD-1 to tryptase and PAR-2 AP were associated with the phosphorylation of MEK and MAP kinase. Inhibition of MEK by PD98059 completely inhibited the proliferationenhancing effects of tryptase and PAR-2 AP as well as phosphorylation of MAP kinase. Moreover, tryptase and PAR-2 AP stimulated the production of prostaglandin E 2 and the inhibition of prostaglandin synthesis by indomethacin or NS398 resulted in the complete inhibition of the proliferative responses to tryptase and PAR-2 AP. Furthermore, the tryptase-stimulated proliferation of DLD-1 was concentration-dependently inhibited by nafamostat mesilate, a specific inhibitor of tryptase. These results as a whole indicated that tryptase has proliferative effects on DLD-1 through cyclooxygenase-and MAP kinase-dependent manners acting on PAR-2 by its proteolytic activity.

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Section: Discussionsupporting

confidence: 57%

Section: +mentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Mast Cell Tryptase Stimulates DLD-1 Carcinoma Through Prostaglandin- and MAP Kinase-Dependent Manners

et al. 2005

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“…PAR 2 , one of the four members of this receptor family, can be activated by trypsin (3), tryptase (4), and the tumor-derived proteinase matriptase (5) to stimulate processes ranging from inflammation and pain perception to tumorigenesis (3,(7)(8)(9). Tumor cells, especially those of epithelial origin, express a high level of PAR 2 (10,11).…”

mentioning

confidence: 99%

Proteinase-activated Receptor-2 Induces Cyclooxygenase-2 Expression through β-Catenin and Cyclic AMP-response Element-binding Protein

Wang

Wen

Bunnett

et al. 2008

Journal of Biological Chemistry

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Chronic inflammation of mucosae is associated with an increased cancer risk. Tumorigenesis in these tissues is associated with the activity of some proteinases, cyclooxygenase-2 (COX-2), and ␤-catenin. Serine proteinases participate in both inflammation and tumorigenesis through the activation of proteinase-activated receptor-2 (PAR 2 ), which up-regulates COX-2 by an unknown mechanism. We sought to determine whether ␤-catenin participated in PAR 2 -induced COX-2 expression and through what cellular mechanism. In A549 epithelial cells, we showed that PAR 2 activation increased COX-2 expression through the ␤-catenin/T cell factor transcription pathway. This effect was dependent upon ERK1/2 MAPK, which inhibited the ␤-catenin-regulating protein, glycogen synthase kinase-3␤, and induced the activity of the cAMP-response element-binding protein (CREB). Knockdown of CREB by small interfering RNA revealed that PAR 2 -induced ␤-catenin transcriptional activity and COX-2 expression were CREB-dependent. A co-immunoprecipitation assay revealed a physical interaction between CREB and ␤-catenin. Thus, PAR 2 up-regulated COX-2 expression via an ERK1/2-mediated activation of the ␤-catenin/Tcf-4 and CREB pathways. These findings reveal new cellular mechanisms by which serine proteinases may participate in tumor development and are particularly relevant to cancers associated with chronic mucosal inflammation, where serine proteinases are abundant and COX-2 overexpression is a common feature.Patients with chronic inflammatory diseases of mucosae, including those of the airway and intestine, have an increased risk for the development of cancer. Serine proteinases have been implicated as key factors in mucosal inflammation and the formation and metastasis of tumors. These proteinases trigger specific cellular responses through proteinase-activated receptors (PARs), 3 G-protein-coupled receptors that are activated by proteolytic cleavage of the extracellular N terminus at a specific amino acid sequence, revealing a new N-terminal "tethered ligand" that binds to and activates the receptor (1, 2). PAR 2 , one of the four members of this receptor family, can be activated by trypsin (3), tryptase (4), and the tumor-derived proteinase matriptase (5) to stimulate processes ranging from inflammation and pain perception to tumorigenesis (3, 7-9). Tumor cells, especially those of epithelial origin, express a high level of PAR 2 (10, 11). Trypsin and matriptase are commonly overexpressed in tumor cells and in their microenvironment at concentrations compatible with PAR 2 activation (12, 13).We have shown previously that the activation of PAR 2 stimulates COX-2 expression (14). COX-2 is expressed early in carcinogenesis and very likely plays a role in the development of cancer (15-17), as it correlates with tumor invasion and poor clinical outcome (18). The mechanisms by which PAR 2 activation induces the expression of COX-2 are still unclear. However, it is known that the cox2 gene can be induced by the transcriptional activity of ␤-catenin....

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“…Vascular endothelial cell is the barrier between blood and vessel wall. Tryptase decreases the barrier function and increases the permeability of endothelial monolayer (Sendo et al, 2003). The dysfunction of vascular endothelial cells plays an important role in vascular inflammation.…”

Section: Introductionmentioning

confidence: 99%

Effects of RNA interference-induced tryptase down-regulation in P815 cells on IL-6 and TNF-α release of endothelial cells

Jiang

Zhao

et al. 2008

J. Zhejiang Univ. Sci. B

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Abstract:Objective: To explore the effects of down-regulated tryptase expression in mast cells on the synthesis and release of interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-α) of vascular endothelial cells. Methods: Tryptase-siRNA (small-interfering RNA) vector was constructed to inhibit tryptase expression in P815 cells. The medium of P815 cells treated by the tryptase-siRNA (RNAi-P815 group) or pure vector (P815 group) was collected and used to culture bEnd.3 cells. The messenger RNAs (mRNAs) of IL-6 and TNF-α in bEnd.3 cells and their protein levels in the medium were measured by reverse transcription polymerase chain reaction (RT-PCR) and enzyme-linked immunosorbent assay (ELISA), respectively. Results: IL-6 and TNF-α mRNAs in bEnd.3 cells cultured in RNAi-P815-conditioned medium decreased significantly compared to those in P815-conditioned medium. Consistently, IL-6 and TNF-α protein levels in the medium of bEnd.3 of RNAi-P815 group were lower than those of P815 group. Conclusion: Reduced tryptase expression significantly inhibited the synthesis and release of IL-6 and TNF-α in vascular endothelial cells. RNA interference targeting tryptase expression may be a new anti-inflammatory strategy for vascular diseases.

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Involvement of proteinase-activated receptor-2 in mast cell tryptase-induced barrier dysfunction in bovine aortic endothelial cells

Cited by 35 publications

References 40 publications

Mast Cell Tryptase Stimulates DLD-1 Carcinoma Through Prostaglandin- and MAP Kinase-Dependent Manners

Mast Cell Tryptase Stimulates DLD-1 Carcinoma Through Prostaglandin- and MAP Kinase-Dependent Manners

Proteinase-activated Receptor-2 Induces Cyclooxygenase-2 Expression through β-Catenin and Cyclic AMP-response Element-binding Protein

Effects of RNA interference-induced tryptase down-regulation in P815 cells on IL-6 and TNF-α release of endothelial cells

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