Proteinase-activated Receptor-2-mediated Activation of Stress-activated Protein Kinases and Inhibitory κB Kinases in NCTC 2544 Keratinocytes

Kanke, Toru; Macfarlane, Scott R.; Seatter, Michael J.; Davenport, Emma L.; Paul, Andrew; McKenzie, Roderick C.; Plevin, Robin

doi:10.1074/jbc.m100377200

Cited by 107 publications

(85 citation statements)

References 62 publications

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“…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. Thus, it is conceivable that the activation of oral epithelial cells by PR3 is mediated by these pathways involved in producing inflammatory cytokines and expressing adhesion molecules on the cell surface.…”

Section: Discussionmentioning

confidence: 99%

“…It was recently reported that stimulation of PAR-2 with an agonist peptide activates human keratinocytes (42), eosinophils (50), and respiratory epithelial cells (51) to induce inflammatory mediators, and up-regulates keratinocyte phagocytosis (52). PR3 is a major target Ag of antineutrophil cytoplasmic Abs (15, 16) and degrades extracellular matrix proteins (13).…”

Section: Discussionmentioning

confidence: 99%

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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: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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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“…There is substantial evidence to suggest that the signaling mechanisms leading to the protective vs degenerative effects of TNF-␣, involves NF B vs death domain-mediated signaling (65,71). Whether activation of PAR-2, as a potential NF-B activator (55,72), may tip the balance of TNF-␣ signaling from death domain-mediated signaling toward NF-B-mediated signaling, is an interesting question to explore in future.…”

Section: Discussionmentioning

confidence: 99%

Proteinase-Activated Receptor-2 Induction by Neuroinflammation Prevents Neuronal Death during HIV Infection

Noorbakhsh

Vergnolle

McArthur

et al. 2005

The Journal of Immunology

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Proteinase-activated receptors (PARs), a newly discovered subgroup of G-protein coupled receptors, are widely expressed by neural cells, but their roles in the nervous system remain uncertain. In this study, we report that PAR-2 was up-regulated on neurons in conjunction with neuroinflammation in brain tissue from patients with HIV-1-associated dementia. The inflammatory cytokines TNF-α and IL-1β were also increased in HIV-1-associated dementia brains compared with patients without dementia (p < 0.05), but these same cytokines induced PAR-2 expression on neurons. Enhanced PAR-2 expression and subsequent activation prevented neuronal cell death and induction of the tumor suppressor, p53, caused by the HIV-encoded protein, Tat (p < 0.01). Intrastriatal implantation of a PAR-2 peptide agonist also inhibited Tat-induced neurotoxicity in a mouse model of HIV neuropathogenesis (p < 0.05). Moreover, PAR-2 null animals showed more severe neuroinflammation and neuronal loss caused by Tat neurotoxicity (p < 0.05). TNF-α protected wild-type neurons from Tat-related neurotoxicity, but in PAR-2-deficient neurons, the same concentrations of TNF-α were cytotoxic (p < 0.001). Thus, neuroinflammation can exert protective effects by which it induces PAR-2 expression with the ensuing abrogation of neuronal death.

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“…For example, trypsin and PAR-2 agonist SLIGKV stimulated a time-dependent increase in p38 MAPK activity in the human keratinocyte cell line NCTC2544, and PAR-2 activation drove pancreatic cancer cell migration via the EGF-Src-Rac-p38 signaling pathway. 35,52 In contrast, activated protein Cemediated activation of PAR-2 inhibited the phosphorylation of p38 in human primary keratinocytes. 53 Therefore, p38 signaling, modulated by PAR-2 activation, may be highly dependent on the cellular context or type.…”

Section: Discussionmentioning

confidence: 95%

“…Previous studies suggested that PAR-2 activates p38 MAPK signaling. 35 PAR-2 is widely expressed in the skin and activated by trypsin-like proteases. 27 Thus, we hypothesized that activation of p38 MAPK signaling in HAI-1 KD HaCaT cells may be caused by inadequate activity of trypsinlike serine protease(s) in the absence of sufficient HAI-1.…”

Section: Enhanced P38 Mapk Activation In Hai-1edeficient Keratinocytementioning

confidence: 99%

Hepatocyte Growth Factor Activator Inhibitor Type 1 Maintains the Assembly of Keratin into Desmosomes in Keratinocytes by Regulating Protease-Activated Receptor 2–Dependent p38 Signaling

Kawaguchi

Kanemaru

Sawaguchi

et al. 2015

The American Journal of Pathology

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Hepatocyte growth factor activator inhibitor type 1 (HAI-1; official symbol SPINT1) is a membraneassociated serine proteinase inhibitor abundantly expressed in epithelial tissues. Genetically engineered mouse models demonstrated that HAI-1 is critical for epidermal function, possibly through direct and indirect regulation of cell surface proteases, such as matriptase and prostasin. To obtain a better understanding of the role of HAI-1 in maintaining epidermal integrity, we performed ultrastructural analysis of Spint1-deleted mouse epidermis and organotypic culture of an HAI-1 knockdown (KD) human keratinocyte cell line, HaCaT. We found that the aggregation of tonofilaments to desmosomes was significantly reduced in HAI-1edeficient mouse epidermis with decreased desmosome number. Similar findings were observed in HAI-1 KD HaCaT organotypic cultures. Immunoblot and immunohistochemical analyses revealed that p38 mitogen-activated protein kinase was activated in response to HAI-1 insufficiency. Treatment of HAI-1 KD HaCaT cells with a p38 inhibitor abrogated the above-observed ultrastructural abnormalities. The activation of p38 induced by the loss of HAI-1 likely resulted from enhanced signaling of protease-activated receptor-2 (PAR-2), because its silencing abrogated the enhanced activation of p38. Consequently, treatment of HAI-1 KD HaCaT cells with a serine protease inhibitor, aprotinin, or PAR-2 antagonist alleviated the abnormal ultrastructural phenotype in organotypic culture. These results suggest that HAI-1 may have a critical role in maintaining normal keratinocyte morphology through regulation of PAR-2edependent p38 mitogen-activated protein kinase signaling. Human skin protects the body from both water loss and mechanical damage. This barrier function is primarily accomplished by the epidermis, a self-renewing stratified squamous epithelium composed of several layers of keratinocytes. 1 To achieve the barrier functions, keratinocytes form dynamic and strong cell-cell junctions in which desmosomes and the network of keratin intermediate filaments (KIFs) are essential to maintain junctional integrity. 2 KIFs are anchored to the cytoplasm and interact with desmosomal cell-cell contacts at the plasma membrane. These are important for mechanical stability of cell-cell contacts between keratinocytes. 3 Disturbance of the integrity of the KIF network leads to skin-blistering diseases, such as epidermolysis bullosa simplex. 4 Although it is not known how KIF disassembly is regulated, recent studies suggested that p38 mitogen-activated protein kinase (MAPK) signaling is involved in these processes. 4e6 The p38 is a member of the MAPK family. It is present in epithelial cells, responds rapidly to various types of stresses,

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Proteinase-activated Receptor-2-mediated Activation of Stress-activated Protein Kinases and Inhibitory κB Kinases in NCTC 2544 Keratinocytes

Cited by 107 publications

References 62 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

Proteinase-Activated Receptor-2 Induction by Neuroinflammation Prevents Neuronal Death during HIV Infection

Hepatocyte Growth Factor Activator Inhibitor Type 1 Maintains the Assembly of Keratin into Desmosomes in Keratinocytes by Regulating Protease-Activated Receptor 2–Dependent p38 Signaling

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