Protease-activated receptors: sentries for inflammation?

Cocks, T. M.; Moffatt, James D.

doi:10.1016/s0165-6147(99)01440-6

Cited by 203 publications

(164 citation statements)

References 42 publications

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“…Moreover the cells responded with proliferation and the release of cytokines, a major executive feature of activated microglia. Induction of cytokines by thrombin would agree with an assumed profile as a proinflammatory signal (5)(6)(7)(8)10).…”

supporting

confidence: 58%

“…Similarly, testing a panel of PAR agonists, i.e. short peptides derived from the tethered ligands that directly activate the receptors (1, 5), we could not trigger release responses, although sequences and concentrations were proven effective in mouse cells (6,44) (data not shown). Microglial PARs must thus serve other thrombin effects, and their expression has also been established for astrocytes and neurons (1, 5, 16 -18, 45-47).…”

Section: Thrombin As An Assumed Activator Of Microglial Releasementioning

confidence: 93%

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The Microglia-activating Potential of Thrombin

Hanisch

Rossum

Xie

et al. 2004

Journal of Biological Chemistry

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The serine protease thrombin is known as a blood coagulation factor. Through limited cleavage of proteinase-activated receptors it can also control growth and functions in various cell types, including neurons, astrocytes, and microglia (brain macrophages). A number of previous studies indicated that thrombin induces the release of proinflammatory cytokines and chemokines from microglial cells, suggesting another important role for the protease beyond hemostasis. In the present report, we provide evidence that this effect is not mediated by any proteolytic or non-proteolytic mechanism involving thrombin proper. Inhibition of the enzymatic thrombin activity did not affect the microglial release response. Instead the cyto-/chemokine-inducing activity solely resided in a high molecular weight protein fraction that could be isolated in trace amounts even from apparently homogenous ␣-and ␥-thrombin preparations. High molecular weight material contained thrombin-derived peptides as revealed by mass spectrometry but was devoid of thrombin-like enzymatic activity. Separated from the high molecular weight fraction by fast protein liquid chromatography, enzymatically intact ␣-and ␥-thrombin failed to trigger any release. Our findings may force a revision of the notion that thrombin itself is a direct proinflammatory release signal for microglia. In addition, they could be relevant for the study of other cellular activities and their assignment to this protease.

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supporting

confidence: 58%

Section: Thrombin As An Assumed Activator Of Microglial Releasementioning

confidence: 93%

The Microglia-activating Potential of Thrombin

Hanisch

Rossum

Xie

et al. 2004

Journal of Biological Chemistry

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“…This finding naturally indicates that the DNFB-and chymase-induced eosinophil accumulation in mice is, at least in part, due to the chemotactic activity of chymase. The direct action of chymase in stimulating eosinophil migration might be mediated via putative receptor(s), such as protease-activated receptor(s) (PAR) (Cocks and Moffatt, 2000) like cathepsin G, an enzyme closely related to chymase, which acts on the platelet by interacting with PAR-4 (Sambrano et al, 2000). An alternative explanation for chymase-induced eosinophil migration is that chymase promotes production of chemokines such as eotaxin.…”

Section: Discussionmentioning

confidence: 99%

Chymase Participates in Chronic Dermatitis by Inducing Eosinophil Infiltration

Tomimori

Muto

Fukami

et al. 2002

Laboratory Investigation

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SUMMARY:An epicutaneous application of 2,4-dinitrofluorobenzene (DNFB) to a mouse ear caused a transient skin swelling, and the repetition of the challenge enlarged the contact dermatitis. The repeated challenge with DNFB also induced eosinophil infiltration on the application site. Administration of a chymase inhibitor significantly inhibited the ear swelling as well as eosinophil accumulation. An intradermal injection of human chymase to the mouse ear also elicited transient skin swelling and eosinophil infiltration, both of which were augmented in proportion to the number of injections. Human serum albumin and heat-inactivated chymase failed to induce such skin reactions, suggesting the participation of proteolytic activity of the enzyme. In addition, chymase stimulated eosinophil migration in vitro in a concentration-dependent manner. Taken together, these observations suggest that mast cell chymase may contribute to development of the DNFB-induced dermatitis, probably by promoting eosinophil infiltration. It is therefore possible that chymase plays a role in pathogenesis of chronic dermatitis such as atopic dermatitis. (Lab Invest 2002, 82:789 -794).A topic dermatitis (AD) is a chronic eczematous skin disorder characterized by dry and itchy skin. The patients with AD often have a family history of other allergic diseases including asthma and hay fever. Although AD is known to be a manifestation of immediate hypersensitivity mediated by IgE, delayed-type hypersensitivity is also involved in the skin reaction of the patients (Tanaka et al, 1994;Varela et al, 1999). Interestingly, in mice, repeated application of contact sensitizing agents, such as 2,4-dinitrofluorobenzene (DNFB) and trinitrochlorobenzene, develops an immediate-type reaction, in contrast to a single application that causes a typical delayed-type reaction (Kitagaki et al, 1995(Kitagaki et al, , 1997. Repeated elicitation with such agents not only increases the serum level of IgE but also induces Th2-type cytokine expression (Nagai et al, 1997b). In addition, mast cell accumulation occurs in the dermis because of the repeated challenge (Kitagaki et al, 1995), as is often observed in AD patients. Therefore, this animal model is thought to be valuable for studying human AD.Chymase is a chymotrypsin-like serine protease and is primarily stored in secretory granules of mast cells (Schwartz and Austen, 1980). Chymase cleaves a variety of physiological substances, including metalloproteases (Fang et al, 1997), procollagen (Kofford et al, 1997), precursor of interleukin 1␤ (IL-1␤) (Mizutani et al, 1991b), and membrane-associated stem cell factor (Longley et al, 1997), while its precise role is not clear. Human mast cells are classified into two types, MC TC and MC T , based on their composition of serine protease (Irani et al, 1986). MC TC contains both chymase and tryptase, while MC T expresses tryptase but not chymase. Because MC TC predominates in the skin (Irani et al, 1989), chymase has been implicated in the pathogenesis of skin disorders complic...

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“…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)(8)(9).…”

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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Protease-activated receptors: sentries for inflammation?

Cited by 203 publications

References 42 publications

The Microglia-activating Potential of Thrombin

The Microglia-activating Potential of Thrombin

Chymase Participates in Chronic Dermatitis by Inducing Eosinophil Infiltration

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

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