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Protease and inflammation

Lukas Winkelsett, Peter Malfertheiner, Thomas Wex, Arne Kandulski
BACKGROUND: Activation of protease-activated receptor-2 (PAR2) is involved in the mucosal immune pathogenesis of gastroesophageal reflux disease (GERD) that is characterized by proinflammatory cytokines such as interleukin-8 (IL-8). PAR2 activation on epithelial cells induces epithelial IL-8 secretion and initiates mucosal inflammation. METHODS: A human primary esophageal epithelial cell model was established to investigate the effects of repeated stimulation with weakly acidic solutions and subsequent PAR2 activation...
April 19, 2018: Digestion
Vijay Kondreddy, Jue Wang, Shiva Keshava, Charles T Esmon, L Vijaya Mohan Rao, Usha R Pendurthi
Recent studies show that endothelial cell protein C receptor (EPCR) interacts with diverse ligands, in addition to its known ligands protein C and activated protein C (APC). We showed in earlier studies that procoagulant clotting factor VIIa (FVIIa) binds EPCR and down-regulates EPCR-mediated anticoagulation and induces endothelial barrier protective effect. Here, we investigated the effect of FVIIa interaction with EPCR on endothelial cell inflammation and LPS-induced inflammatory responses in vivo. Treatment of endothelial cells with FVIIa suppressed TNFα- and LPS-induced expression of cellular adhesion molecules and adherence of monocytes to endothelial cells...
April 18, 2018: Blood
Andreea-Manuela Mirea, Cees J Tack, Triantafyllos Chavakis, Leo A B Joosten, Erik J M Toonen
Nonalcoholic fatty liver disease (NAFLD) is the most common liver disease worldwide. Pathways responsible for the activation of IL-1 family cytokines are key in the development of NAFLD but underlying mechanisms are not fully understood. Many studies have focused on the inflammasome-caspase-1 pathway and have shown that this pathway is an important inducer of inflammation in NAFLD. However, this pathway is not solely responsible for the activation of proinflammatory cytokines. Also, neutrophil serine proteases (NSPs) are capable of activating cytokines and recent studies reported that these proteases also contribute to NAFLD...
April 14, 2018: Trends in Molecular Medicine
Samir N Babayev, Mohammed Kanchwala, Chao Xing, Yucel Akgul, Bruce R Carr, Ruth Ann Word
Vaginal bleeding and subchorionic hematomas are associated with increased risk of both early and late pregnancy loss. Thrombin generation may play a pivotal role in the development of these complications. To determine the effects of thrombin on human endometrial stromal cells (hESCs), cells were treated with thrombin at baseline or during decidualization with cyclic adenosine monophosphate (cAMP)+medroxyprogesterone acetate (MPA). Next-generation RNA sequencing revealed that markers of decidualization (IGF-1, IGFBP-1, and prolactin [PRL]) were induced after the initiation of decidualization, whereas thrombin suppressed insulin-like growth factor ( IGF)-1, Insulin-like growth factor binding protein ( IGFBP)-1, and PRL gene expression at baseline and during decidualization...
January 1, 2018: Reproductive Sciences
Yina Li, Laura A Jacox, Shannyn H Little, Ching-Chang Ko
Orthodontic tooth movement relies on coordinated tissue resorption and formation in the surrounding bone and periodontal ligament. Tooth loading causes local hypoxia and fluid flow, initiating an aseptic inflammatory cascade culminating in osteoclast resorption in areas of compression and osteoblast deposition in areas of tension. Compression and tension are associated with particular signaling factors, establishing local gradients to regulate remodeling of the bone and periodontal ligament for tooth displacement...
April 2018: Kaohsiung Journal of Medical Sciences
Yunfeng Chen, Zaverio M Ruggeri, Xiaoping Du
Members of the 14-3-3 family of proteins function as adapters/modulators that recognize phosphoserine/phosphothreonine-based binding motifs in many intracellular proteins and play fundamental roles in signal transduction pathways of eukaryotic cells. In platelets, 14-3-3 plays a wide range of regulatory roles in phosphorylation-dependent signaling pathways, including G-protein signaling, cAMP signaling, agonist-induced phosphatidyl-serine (PS) exposure and regulation of mitochondrial function. In particular, 14-3-3 inter-acts with several phosphoserine-dependent binding sites in the major platelet adhesion re-ceptor, the glycoprotein Ib-IX complex (GPIb-IX), regulating its interaction with von Wil-lebrand factor (VWF) and mediating VWF/GPIb-IX-dependent mechano-signal transduc-tion leading to platelet activation...
April 5, 2018: Blood
Monika Pathak, Bubacarr Gibril Kaira, Alexandre Slater, Jonas Emsley
The contact activation system (CAS) or contact pathway is central to the crosstalk between coagulation and inflammation and contributes to diverse disorders affecting the cardiovascular system. CAS initiation contributes to thrombosis but is not required for hemostasis and can trigger plasma coagulation via the intrinsic pathway [through factor XI (FXI)] and inflammation via bradykinin release. Activation of factor XII (FXII) is the principal starting point for the cascade of proteolytic cleavages involving FXI, prekallikrein (PK), and cofactor high molecular weight kininogen (HK) but the precise location and cell receptor interactions controlling these reactions remains unclear...
2018: Frontiers in Medicine
Ya-Hui Liu, Yung-Chi Chang, Liang-Kuei Chen, Po-An Su, Wen-Chien Ko, Yau-Sheng Tsai, Yi-Hsuan Chen, Hsin-Chih Lai, Cheng-Yeu Wu, Yuan-Pin Hung, Pei-Jane Tsai
Clostridium difficile infection (CDI) is the leading cause of nosocomial infection in hospitalized patients receiving long-term antibiotic treatment. An excessive host inflammatory response is believed to be the major mechanism underlying the pathogenesis of C. difficile infection, and various proinflammatory cytokines such as IL-1β are detected in patients with C. difficile infection. IL-1β is known to be processed by caspase-1, a cysteine protease that is regulated by a protein complex called the inflammasome, which leads to a specialized form of cell death called pyroptosis...
2018: Frontiers in Cellular and Infection Microbiology
Thomas Vogl, Athanasios Stratis, Viktor Wixler, Tom Völler, Sumita Thurainayagam, Selina K Jorch, Stefanie Zenker, Alena Dreiling, Deblina Chakraborty, Mareike Fröhling, Peter Paruzel, Corinna Wehmeyer, Sven Hermann, Olympia Papantonopoulou, Christiane Geyer, Karin Loser, Michael Schäfers, Stephan Ludwig, Monika Stoll, Tomas Leanderson, Joachim L Schultze, Simone König, Thomas Pap, Johannes Roth
Autoimmune diseases, such as psoriasis and arthritis, show a patchy distribution of inflammation despite systemic dysregulation of adaptive immunity. Thus, additional tissue-derived signals, such as danger-associated molecular patterns (DAMPs), are indispensable for manifestation of local inflammation. S100A8/S100A9 complexes are the most abundant DAMPs in many autoimmune diseases. However, regulatory mechanisms locally restricting DAMP activities are barely understood. We now unravel for the first time, to our knowledge, a mechanism of autoinhibition in mice and humans restricting S100-DAMP activity to local sites of inflammation...
April 3, 2018: Journal of Clinical Investigation
Y Jockel-Schneider, A Kobsar, A Stellzig-Eisenhauer, U Vogel, S Störk, S Frantz, U Schlagenhauf, M Eigenthaler
In vitro studies revealed that Porphyromonas gingivalis (Pg), a pathogen intimately associated with the onset and progression of periodontitis, is able to activate platelets thus linking periodontal inflammation with the endangerment of vascular health. As wild-type Pg strains are characterized by major genetic heterogeneity, the commonness of platelet activating Pg strains in periodontitis patients is unknown as of yet. Therefore, this study evaluated the platelet activation capacity of wild-type Pg isolates sampled from patients with aggressive periodontitis...
April 2, 2018: Journal of Clinical Periodontology
Mel Berger, Mingyao Liu, Marc E Uknis, Maria Koulmanda
Limited availability of donor organs and risk of ischemia-reperfusion injury (IRI) seriously restrict organ transplantation. Therapeutics that can prevent or reduce IRI could potentially increase the number of transplants by increasing use of borderline organs and decreasing discards. Alpha-1 antitrypsin (AAT) is an acute phase reactant and serine protease inhibitor which limits inflammatory tissue damage. Purified plasma-derived AAT has been well-tolerated in more than 30 years of use to prevent emphysema in AAT deficient individuals...
April 1, 2018: American Journal of Transplantation
Laurence Glennon-Alty, Angela P Hackett, Elinor A Chapman, Helen L Wright
Polymorphonuclear leukocytes, or neutrophils, are specialist phagocytic cells of the innate immune system. Their primary role is host defence against micro-organisms, which they kill via phagocytosis, followed by release of reactive oxygen species (ROS) and proteolytic enzymes within the phagosome. ROS are generated via the action of the NADPH oxidase (also known as NOX2), in a process termed the 'Respiratory Burst'. This process consumes large amounts of oxygen, which is converted into the highly-reactive superoxide radical O2 - and H2 O2 ...
March 29, 2018: Free Radical Biology & Medicine
Chisa Nakashima, Atsushi Otsuka, Kenji Kabashima
Basophils have been recognized as crucial players in allergic inflammation. Basophils have the potential to initiate and expand inflammation through the production of specific cytokines and proteases, and are associated with T helper 2 (Th2) immune responses. In addition, recent studies revealed the heterogeneity in basophil populations. Basophils have been clarified important roles in not only IgE-mediated allergic inflammation but also TSLP-mediated and IgE-independent inflammation. Moreover, basophils infiltrate in many human cutaneous diseases...
March 13, 2018: Journal of Dermatological Science
Tjie Kok, Anna A Wasiel, Frank J Dekker, Gerrit J Poelarends, Robbert H Cool
The HLA class II histocompatibility antigen gamma chain, also known as HLA-DR antigen-associated invariant chain or CD74, has been shown to be involved in many biological processes amongst which antigen loading and transport of MHC class II molecules from the endoplasmic reticulum to the Golgi complex. It is also part of a receptor complex for Macrophage Migration Inhibitory Factor (MIF), and participates in inflammatory signaling. The inhibition of MIF-CD74 complex formation is regarded as a potentially attractive therapeutic target in inflammation, cancer and immune diseases...
March 27, 2018: Protein Expression and Purification
Laura D Healy, Rachel A Rigg, John H Griffin, Owen J T McCarty
Innate immune cells are an essential part of the host defense response, promoting inflammation through release of proinflammatory cytokines or formation of neutrophil extracellular traps. While these processes are important for defense against infectious agents or injury, aberrant activation potentiates pathologic inflammatory disease. Thus, understanding regulatory mechanisms that limit neutrophil extracellular traps formation and cytokine release is of therapeutic interest for targeting pathologic diseases...
March 30, 2018: Journal of Leukocyte Biology
Shannon M Jones, Adrien Mann, Kelsey Conrad, Keith Saum, David E Hall, Lisa M McKinney, Nathan Robbins, Joel Thompson, Abigail D Peairs, Eric Camerer, Katey J Rayner, Michael Tranter, Nigel Mackman, A Phillip Owens
OBJECTIVE: PAR2 (protease-activated receptor 2)-dependent signaling results in augmented inflammation and has been implicated in the pathogenesis of several autoimmune conditions. The objective of this study was to determine the effect of PAR2 deficiency on the development of atherosclerosis. APPROACH AND RESULTS: PAR2 mRNA and protein expression is increased in human carotid artery and mouse aortic arch atheroma versus control carotid and aortic arch arteries, respectively...
March 29, 2018: Arteriosclerosis, Thrombosis, and Vascular Biology
Caterina Camodeca, Doretta Cuffaro, Elisa Nuti, Armando Rossello
The ADAMs, together with ADAMTSs and snake venom metalloproteases (SVMPs), are members of the Adamalysin family. Differences in structural organization, functions and localization are known and their domains, catalytic or non-catalytic, show key roles in the substrate recognition and protease activity. Some ADAMs, as membrane-bound enzymes, show sheddase activity. Sheddases are key to modulation of functional proteins such as the tumor necrosis factor, growth factors, cytokines and their receptors, adhesion proteins, signaling molecules and stress molecules involved in immunity...
March 26, 2018: Current Medicinal Chemistry
Yichao Zhao, Lingchen Gao, Longwei Xu, Renyang Tong, Nan Lin, Yuanyuan Su, Yang Yan, Yu Gao, Jie He, Lingcong Kong, Ancai Yuan, Ying Zhuge, Fang Wang, Jun Pu
Nonalcoholic fatty liver disease (NAFLD), characterized by hepatic steatosis, insulin resistance and inflammation, poses a high risk of cardiometabolic disorders. Ubiquitin specific protease 4 (USP4), a deubiquitinating enzyme, is pivotally involved in regulating multiple inflammatory pathways; however, the role of USP4 in NAFLD is unknown. Here we report that USP4 expression was dramatically downregulated in the livers from NAFLD patients and different NAFLD mouse models induced by a high fat diet (HFD) or a genetic deficiency (ob/ob) as well as in palmitate-treated hepatocytes...
March 23, 2018: Hepatology: Official Journal of the American Association for the Study of Liver Diseases
Sivasankari Thilagar, Muthukumar Santhanakrishnan, Suresh Rao
Background: Protease-activated receptors (PAR-1 and PAR-2) are found to be immensely exhibited in the periodontal tissues. These receptors are involved in the inflammatory and repair processes. Activation of PARs is mainly by the bacterial and endogenous enzymes. The aim of the study was to determine the role of PAR-1 and PAR-2 in initiating periodontal inflammation and to immunolocalize these receptors in the gingival tissues of healthy and chronic periodontitis individuals. Materials and Methods: A total of 50 patients were selected for this study, of which 25 were healthy controls and 25 were chronic periodontitis patients...
January 2018: Journal of Indian Society of Periodontology
Eva Svandova, Barbora Vesela, Abigail S Tucker, Eva Matalova
Caspases are well known proteases in the context of inflammation and apoptosis. Recently, novel roles of pro-apoptotic caspases have been reported, including findings related to the development of hard tissues. To further investigate these emerging functions of pro-apoptotic caspases, the in vivo localisation of key pro-apoptotic caspases (-3,-6,-7,-8, and -9) was assessed, concentrating on the development of two neighbouring hard tissues, cells participating in odontogenesis (represented by the first mouse molar) and intramembranous osteogenesis (mandibular/alveolar bone)...
2018: Frontiers in Physiology
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