Protease-activated receptor 2 signaling in inflammation

Rothmeier, Andrea S.; Ruf, Wolfram

doi:10.1007/s00281-011-0289-1

Cited by 256 publications

(265 citation statements)

References 204 publications

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“…PAR2 has an established involvement in inflammatory cardiovascular, pulmonary and gastrointestinal diseases and is also involved in neuroinflammation seen in some neurodegenerative disorders, since increased PAR2 expression was found in brain in Alzheimer's disease and multiple sclerosis (Afkhami-Goli et al, 2007;Noorbakhsh et al, 2006;Rothmeier and Ruf, 2012). However, the status of PAR2 in Parkinson's disease is unknown.…”

Section: Introductionmentioning

confidence: 99%

Altered Expression of Brain Proteinase-Activated Receptor-2, Trypsin-2 and Serpin Proteinase Inhibitors in Parkinson’s Disease

et al. 2015

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In neurologically normal brain expression of proteinase-activated receptor-2, activating proteinases and proteinase inhibitors was found in neurons and microglia and did not specifically associate with regions prone to neurodegeneration in Parkinson's disease. InParkinson's disease brain, alterations in the amount of immunoreactivity for proteinaseactivated receptor-2, trypsin-2 and both serpin proteinase inhibitors were found throughout the brain. In neurons, there was a decrease in neurons positive for proteinase inhibitors with increasing Braak α-synuclein stage in the dorsal motor nucleus, locus coeruleus, substantia nigra and primary motor cortex. In contrast, in the cingulate cortex, proteinase-activated receptor-2 expression had a positive correlation to increase with higher Braak α-synuclein stage rating and serpin-A13 was increased in early Parkinson's disease cases compared to controls. In microglia, increased expression occurred for the serpins (dorsal motor nucleus of vagus and substantia nigra), trypsin-2 (dorsal motor nucleus of vagus and primary motor cortex) and proteinase-activated receptor-2 (locus coeruleus and cingulate cortex) that progressively increased with advancing Parkinson's disease severity.In cingulate cortex, the covariate dyskinesia had a significant effect on the the adjusted means for trypsin-2 labelled neurons and microglia and the covariate psychosis had a significant effect on neurons labelled with serpin-A5. While in primary motor cortex, the covariate dyskinesia had a significant effect on the the adjusted means for neurons labelled with serpin-A5, serpin-A13 and trypsin-2. Analysis of Parkinson's disease cases found that serpin and trypsin-2 expression in midbrain and cerebral cortex was different in cases with dyskinesia and psychosis compared to those with no treatment induced side-effects. This study showed that there was altered expression in brain of proteinase-activated receptor-2 and some proteins that can control its function in Parkinson's disease. Given the role of PAR2 expression in Parkinson's disease 3 proteinase-activated receptor-2 in neuroinflammation, drugs that mitigate these changes could be neuroprotective when administered to patients with Parkinson's disease.

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Section: Introductionmentioning

confidence: 99%

Altered Expression of Brain Proteinase-Activated Receptor-2, Trypsin-2 and Serpin Proteinase Inhibitors in Parkinson’s Disease

et al. 2015

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Section: Squamous Cell Carcinoma Of the Oral Cavity (Oscc)mentioning

confidence: 99%

“…Many studies have associated proteinase-activated receptor-2 (PAR-2) with both inflammation and tumor progression (11)(12)(13)(14)(15); however, the expression of PAR-2 in OSCC has not been evaluated. PAR-2 is a G protein-coupled receptor that is activated by trypsin-like serine proteinases.…”

mentioning

confidence: 99%

“…Proteolytic cleavage of the extracellular amino terminus generates a "tethered ligand" that binds to the receptor, initiating G␣ protein signaling. PAR-2 can also be activated by PAR2-activating peptides that mimic the tethered ligand amino acid sequence and generate all of the hallmarks of an inflammatory response (11,12).Kallikrein 5 (KLK5) is a secreted serine protease that is involved in regulated skin desquamation during epidermal differentiation (16). We have previously reported that KLK5 is up-regulated at the mRNA and protein levels in oral cancer cell lines and human OSCC tissues (17) and catalyzes cleavage of the cell-cell adhesion molecule desmoglein-1, promoting loss of junctional integrity and enhanced invasive activity in vitro (18).…”

mentioning

confidence: 99%

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Protease-activated Receptor-2 (PAR-2)-mediated Nf-κB Activation Suppresses Inflammation-associated Tumor Suppressor MicroRNAs in Oral Squamous Cell Carcinoma

Johnson

Miller

Jiang

et al. 2016

Journal of Biological Chemistry

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Oral cancer is the sixth most common cause of death from cancer with an estimated 400,000 deaths worldwide and a low (50%) 5-year survival rate. The most common form of oral cancer is oral squamous cell carcinoma (OSCC). OSCC is highly inflammatory and invasive, and the degree of inflammation correlates with tumor aggressiveness. The G protein-coupled receptor protease-activated receptor-2 (PAR-2) plays a key role in inflammation. PAR-2 is activated via proteolytic cleavage by trypsin-like serine proteases, including kallikrein-5 (KLK5), or by treatment with activating peptides. PAR-2 activation induces G protein-␣-mediated signaling, mobilizing intracellular calcium and Nf-B signaling, leading to the increased expression of pro-inflammatory mRNAs. Little is known, however, about PAR-2 regulation of inflammation-related microRNAs. Here, we assess PAR-2 expression and function in OSCC cell lines and tissues. Stimulation of PAR-2 activates Nf-B signaling, resulting in RelA nuclear translocation and enhanced expression of pro-inflammatory mRNAs. Concomitantly, suppression of the anti-inflammatory tumor suppressor microRNAs let-7d, miR-23b, and miR-200c was observed following PAR-2 stimulation. Analysis of orthotopic oral tumors generated by cells with reduced KLK5 expression showed smaller, less aggressive lesions with reduced inflammatory infiltrate relative to tumors generated by KLK5-expressing control cells. Together, these data support a model wherein KLK5-mediated PAR-2 activation regulates the expression of inflammation-associated mRNAs and microRNAs, thereby modulating progression of oral tumors. Squamous cell carcinoma of the oral cavity (OSCC)2 is a highly inflammatory disease that ranks as the 6th most frequently diagnosed cancer worldwide, with a poor 5-year survival rate of about 50% (1). Early diagnosis of OSCC is challenging, predominantly because early oral cancers and premalignant lesions are often subtle and asymptomatic. Although many patients present for diagnosis with stage III or IV disease, premalignant lesions in the oral mucosa often precede invasive OSCC (2). Furthermore, unlike most solid tumors that are monoclonal in origin, multiple distinct foci of dysplastic cells may be present in the oral mucosa. These epithelial dysplasia are categorized as mild, moderate, severe, or carcinoma in situ based on the histologic abnormalities present in the oral epithelium (3). Studies show that ϳ12-36% of epithelial dysplasia progress to carcinoma (4, 5); however, current approaches do not enable accurate identification of premalignant lesions likely to undergo malignant transformation.The link between inflammation and cancer is now well established, and inflammatory mediators are present in the microenvironment of virtually all solid tumors (6 -10). Many studies have associated proteinase-activated receptor-2 (PAR-2) with both inflammation and tumor progression (11-15); however, the expression of PAR-2 in OSCC has not been evaluated. PAR-2 is a G protein-coupled receptor that is activated by trypsin-...

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“…Proteinase-activated receptor-2 (PAR-2) is a seven-transmembrane domain receptor family which couples to G-proteins [20]. Rgps are capable of activating PAR-2 expressed on human gingival epithelial cells, which produce proinflammatory cytokines [21].…”

Section: Role Of Par-2 In the Induction Of Il-33 By Gingipainsmentioning

confidence: 99%

Possible Roles of IL-33 in Periodontal Diseases: Porphyromonas gingivalis Induced IL-33 in Human Gingival Epithelial Cells

Tada

Shimauchi

Takada

et al. 2015

Interface Oral Health Science 2014

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In the oral mucosa, epithelial cells work not only as a physical barrier to pathogens, but also play a pivotal role in initiating immune responses to microbes. Interleukin (IL)-33, a member of the IL-1 family, is constitutively expressed in epithelial cells and amplifies Th2-type inflammatory immune responses. We found that IL-33 was detected in the inflamed gingival epithelium from chronic periodontitis patients, and periodontopathic Porphyromonas gingivalis strongly increased expressions of IL-33 mRNA and molecules in human gingival epithelial cells. In contrast, fimbriae, a lipopeptide and lipopolysaccharide derived from P. gingivalis were not active in this respect. Protease inhibitors specific for gingipains efficiently inhibited the induction of IL-33 mRNA by stimulation with P. gingivalis. Furthermore, P. gingivalis KDP136, a gingipains-null mutant, did not increase IL-33 mRNA expression. We also demonstrated that P. gingivalis upregulated IL-33 mRNA expression through protease-activated receptor-2, phospholipase C, mitogen-activated protein kinase p38 and NF-κB. IL-33 is suggested to negatively regulate antimicrobial peptide LL-37, resulting in attenuation of innate immune responses of gingival epithelial cells in chronic periodontitis. Possible roles of IL-33 in inflammation in the oral mucosa are discussed.

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Protease-activated receptor 2 signaling in inflammation

Cited by 256 publications

References 204 publications

Altered Expression of Brain Proteinase-Activated Receptor-2, Trypsin-2 and Serpin Proteinase Inhibitors in Parkinson’s Disease

Altered Expression of Brain Proteinase-Activated Receptor-2, Trypsin-2 and Serpin Proteinase Inhibitors in Parkinson’s Disease

Protease-activated Receptor-2 (PAR-2)-mediated Nf-κB Activation Suppresses Inflammation-associated Tumor Suppressor MicroRNAs in Oral Squamous Cell Carcinoma

Possible Roles of IL-33 in Periodontal Diseases: Porphyromonas gingivalis Induced IL-33 in Human Gingival Epithelial Cells

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