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Marta Stolarczyk, Bob J Scholte
Chronic obstructive pulmonary disease (COPD) and cystic fibrosis (CF) share molecular mechanisms that cause the pathological symptoms they have in common. Here, we review evidence suggesting that hyperactivity of the EGFR/ADAM17 axis plays a role in the development of chronic lung disease in both CF and COPD. The ubiquitous transmembrane protease A disintegrin and metalloprotease 17 (ADAM17) forms a functional unit with the EGF receptor (EGFR), in a feedback loop interaction labeled the ADAM17/EGFR axis. In airway epithelial cells, ADAM17 sheds multiple soluble signaling proteins by proteolysis, including EGFR ligands such as amphiregulin (AREG), and proinflammatory mediators such as the interleukin 6 coreceptor (IL-6R)...
2018: Mediators of Inflammation
Won Seok Yang, Jin Ju Kim, Mee Jeong Lee, Eun Kyoung Lee, Su-Kil Park
BACKGROUND/AIMS: Lipopolysaccharide (LPS)-activated monocytes/macrophages develop endotoxin tolerance in part by reducing cell surface toll-like receptor 4 (TLR4) through cluster of differentiation 14 (CD14)-dependent endocytosis. In case of endothelial cells, CD14 is expressed in low copy numbers as compared with monocytes/macrophages. Thus, we explored how endothelial cells regulate TLR4 expression after LPS stimulation. METHODS: Cultured human aortic endothelial cells (HAECs) were treated with LPS...
February 28, 2018: Cellular Physiology and Biochemistry
Maocai Zhai, Junyi Guo, Haiyan Ma, Wei Shi, David Jou, Dan Yan, Tianshu Liu, Jingwen Tao, Jialin Duan, Yina Wang, Sheng Li, Jiagao Lv, Chenglong Li, Jiayuh Lin, Cuntai Zhang, Li Lin
BACKGROUND AND AIMS: Abdominal aortic aneurysms (AAA) is a chronic inflammatory disease in which signal transducer and activator of transcription 3 (STAT3), and disintegrin and metalloproteinase 17 (ADAM17) play important roles. However, it remains unclear whether ursolic acid (UA), a natural pentacyclic triterpenoid carboxylic acid, can have an impact on STAT3 and ADAM17 and hence influence the formation of AAA. The objective of this study was to characterize the potential effect of UA on the pathogenesis of AAA and on STAT3 and ADAM17...
February 15, 2018: Atherosclerosis
W Y Fang, C W Lin, B F Wang, S G Feng
Objective: Construct a paraquat (PQ) cell fibrosis model in vitro, observe the effect of PQ on the expression of a disintegrin and metalloproteinase-17 (ADAM17) in A549 cells, and explore the role of ADAM17 in the pulmonary fibrosis induced by PQ poisoning. Methods: A549 cells are divided into normal control group, different concentration of PQ groups, CCK-8 is used to detect cell viability, screening concentration and time of PQ, cell morphology is observed under microscope; Enzyme-linked immunosorbent assay (ELISA) detectes fibrosis markers of collagen type I (Col I) and fibronectin (FN) expression...
January 20, 2018: Chinese Journal of Industrial Hygiene and Occupational Diseases
Jian Zhang, Longjun Guo, Lijun Yang, Jiayu Xu, Lu Zhang, Li Feng, Hongyan Chen, Yue Wang
Porcine epidemic diarrhea virus (PEDV) is a causative agent of porcine epidemic diarrhea (PED). PED, characterized by acute diarrhea, vomiting, dehydration, has caused serious economic losses in pig industry worldwide. Here, we demonstrate that activation of a disintergrin and metalloprotease 17 (ADAM17) induced the decrease of PEDV infection in HEK293 and IPEC-J2 cells and the downregulation of cell surface aminopeptidase N (APN) expression, an important entry factor for PEDV infection. Furthermore, overexpression of ADAM17 suppressed PEDV infection in HEK293 and IPEC-J2 cells, whereas ablation of ADAM17 expression using ADAM17 specific siRNA resulted in a corresponding increase of PEDV infection and an upregulation of cell surface APN expression...
February 20, 2018: Virology
Stefanie Schmidt, Neele Schumacher, Jeanette Schwarz, Simone Tangermann, Lukas Kenner, Michaela Schlederer, Maria Sibilia, Markus Linder, Annelore Altendorf-Hofmann, Thomas Knösel, Elisabeth S Gruber, Georg Oberhuber, Julia Bolik, Ateequr Rehman, Anupam Sinha, Juliane Lokau, Philipp Arnold, Anne-Sophie Cabron, Friederike Zunke, Christoph Becker-Pauly, Adele Preaudet, Paul Nguyen, Jennifer Huynh, Shoukat Afshar-Sterle, Ashwini L Chand, Jürgen Westermann, Peter J Dempsey, Christoph Garbers, Dirk Schmidt-Arras, Philip Rosenstiel, Tracy Putoczki, Matthias Ernst, Stefan Rose-John
Colorectal cancer is treated with antibodies blocking epidermal growth factor receptor (EGF-R), but therapeutic success is limited. EGF-R is stimulated by soluble ligands, which are derived from transmembrane precursors by ADAM17-mediated proteolytic cleavage. In mouse intestinal cancer models in the absence of ADAM17, tumorigenesis was almost completely inhibited, and the few remaining tumors were of low-grade dysplasia. RNA sequencing analysis demonstrated down-regulation of STAT3 and Wnt pathway components...
February 22, 2018: Journal of Experimental Medicine
Maria Vila-Casadesús, Elena Vila-Navarro, Giulia Raimondi, Cristina Fillat, Antoni Castells, Juan José Lozano, Meritxell Gironella
MiRNAs are small non-coding RNAs that post-transcriptionally regulate gene expression. They play important roles in cancer but little is known about the specific functions that each miRNA exerts in each type of cancer. More knowledge about their specific targets is needed to better understand the complexity of molecular networks taking part in cancer. In this study we report the miRNA-mRNA interactome occurring in pancreatic cancer by using a bioinformatic approach called miRComb, which combines tissue expression data with miRNA-target prediction databases (TargetScan, miRSVR and miRDB)...
January 19, 2018: Oncotarget
Nuray Erin, Sema Türker, Özlem Elpek, Bülent Yildirim
ADAM metallopeptidase domain (ADAM)9, 10 and 17 have α-secretase activity that regulates ectodomain shedding of factors involved in inflammation, cell proliferation, angiogenesis, and wound healing. The secretase activity of ADAM proteins is known to induce an inflammatory response. However, under certain conditions, a lack of secretase activity may induce inflammation suggesting differential roles of ADAM proteins with secretase activity. To the best of our knowledge, the present study evaluated the changes in α-secretase activity and expression of associated ADAM proteases (ADAM9, 10 and 17) in the gastric mucosa of patients with gastritis and ulcers, for the first time...
February 2018: Experimental and Therapeutic Medicine
Baoshan Hu, Xiangchao Meng, Yan Zhang, Mohammad Monir Hossain, Lijun Wu, Yuanyuan Zhang, Xiaobing Peng, Xuepeng Zhang
A disintegrin and metalloprotease 17 (ADAM17) is highly expressed in many malignant tumors and is closely related to their development. We showed in a previous study that silencing of ADAM17 by siRNA inhibited the growth of MCF‑7 breast cancer cells in vitro and in vivo. In the present study, we investigated the effects of ADAM17-short hairpin RNA (ADAM17‑shRNA) on MCF‑7 breast cancer cells and explored the potential action pathway. In vitro, transfection of shRNAs was performed using a lentivirus, and the effects of ADAM17‑shRNA on invasion, proliferation and cell cycle distribution of MCF‑7 cells were assessed by Boyden chamber method, real‑time cell analysis and flow cytometry, respectively...
January 26, 2018: Oncology Reports
Xiaoping Qing, Yurii Chinenov, Patricia Redecha, Michael Madaio, Joris Jth Roelofs, Gregory Farber, Priya D Issuree, Laura Donlin, David R McIlwain, Tak W Mak, Carl P Blobel, Jane E Salmon
Lupus nephritis (LN) often results in progressive renal dysfunction. The inactive Rhomboid 2 (iRhom2) is a newly identified key regulator of A disintegrin and metalloprotease 17 (ADAM17), whose substrates, such as TNF-α and heparin-binding EGF (HB-EGF), have been implicated in the pathogenesis of chronic kidney disease. Here we demonstrate that deficiency of iRhom2 protects the lupus-prone Fcgr2b-/- mice from developing severe kidney damage without altering anti-double stranded (ds) DNA Ab production, by simultaneously blocking the HB-EGF/EGFR and the TNF-α signaling in the kidney tissues...
January 25, 2018: Journal of Clinical Investigation
Renzhong Li, Tony Wang, Khyati Walia, Bo Gao, Joan C Krepinsky
Glomerular matrix accumulation is the hallmark of diabetic nephropathy. The metalloprotease ADAM17 mediates high glucose (HG)-induced matrix production by kidney mesangial cells through release of ligands for the epidermal growth factor receptor. Here we study the mechanism by which HG activates ADAM17. We find that the C-terminus is essential for ADAM17 activation and the profibrotic response to HG. In the C-terminus, Src-mediated Y702 phosphorylation and PI3K/MEK/Erk-mediated T735 phosphorylation are critical to ADAM17 activation, but play divergent roles in ADAM17 trafficking in response to HG...
January 12, 2018: Journal of Cell Science
Marta Stolarczyk, Guido Veit, Andrea Schnur, Mieke Veltman, Gergely L Lukacs, Bob J Scholte
The EGFR/ADAM17 signaling pathway mediates the shedding of growth factors and secretion of cytokines, and is involved in chronic inflammation and tissue remodeling. Since these are hallmarks of cystic fibrosis (CF) lung disease, we hypothesized that CFTR deficiency enhances EGFR/ADAM17 activity in human bronchial epithelial cells. In CFBE41o- cells lacking functional CFTR (iCFTR-) cultured at air-liquid interface (ALI) we found enhanced ADAM17-mediated shedding of the EGFR ligand amphiregulin (AREG) compared to genetically identical cells with induced CFTR expression (iCFTR+)...
December 14, 2017: American Journal of Physiology. Lung Cellular and Molecular Physiology
Sebastian Krossa, Axel J Scheidig, Joachim Grötzinger, Inken Lorenzen
A Disintegrin and Metalloprotease 17 (ADAM17) can cause the fast release of growth factors and inflammatory mediators from the cell surface. Its activity has to be turned on which occurs by various stimuli. The active form can be inactivated by a structural change in its ectodomain, related to the pattern of the formed disulphide bridges. The switch-off is executed by protein disulfide isomerases (PDIs) that catalyze an isomerization of two disulfide bridges and thereby cause a disulfide switch. We demonstrate that the integrity of the CGHC-motif within the active site of PDIs is indispensable...
January 18, 2018: Scientific Reports
Daniela Granato, Rute A P Costa, Rebeca Kawahara, Sami Yokoo, Annelize Aragao, Romenia Domingues, Bianca Pauletti, Rodrigo Honorato, Juliana Fattori, Ana Figueira, Paulo Oliveira, Silvio Consonni, Denise Castro Fernandes, Francisco Rafael Martins Laurindo, Hinrich Hansen, Adriana F Paes Leme
A Disintegrin And Metalloprotease 17 (ADAM17) modulates signaling events by releasing surface protein ectodomains such as TNFα and the EGFR-ligands. We have previously characterized cytoplasmic thioredoxin-1 (Trx-1) as a partner of ADAM17 cytoplasmic domain. Combining discovery and targeted proteomic approaches, we uncovered that Trx-1 negatively regulates ADAM17 by direct and indirect effect. We performed cell-based assays with synthetic peptides and site-directed mutagenesis and we demonstrated that the interaction interface of Trx-1 and ADAM17 is important for the negative regulation of ADAM17 activity...
January 15, 2018: Antioxidants & Redox Signaling
Wilbur M Song, Satoru Joshita, Yingyue Zhou, Tyler K Ulland, Susan Gilfillan, Marco Colonna
Alzheimer's disease (AD) is a neurodegenerative disease that causes late-onset dementia. The R47H variant of the microglial receptor TREM2 triples AD risk in genome-wide association studies. In mouse AD models, TREM2-deficient microglia fail to proliferate and cluster around the amyloid-β plaques characteristic of AD. In vitro, the common variant (CV) of TREM2 binds anionic lipids, whereas R47H mutation impairs binding. However, in vivo, the identity of TREM2 ligands and effect of the R47H variant remain unknown...
January 10, 2018: Journal of Experimental Medicine
Justin B Schaal, Thorsten Maretzky, Dat Q Tran, Patti A Tran, Prasad Tongaonkar, Carl P Blobel, André J Ouellette, Michael E Selsted
Theta-defensins (θ-defensins) are macrocyclic peptides expressed exclusively in granulocytes and selected epithelia of Old World monkeys.  They contribute to anti-pathogen host defense responses by directly killing a diverse range of microbes.  Of note, θ-defensins also modulate microbe-induced inflammation by affecting the production of soluble tumor necrosis factor (sTNF) and other proinflammatory cytokines.  Here, we report that natural rhesus macaque θ-defensin (RTD) isoforms regulate sTNF cellular release by inhibiting TNF alpha converting enzyme (TACE; also known as a disintegrin and metalloprotease 17; ADAM17), the primary pro-TNF sheddase...
January 9, 2018: Journal of Biological Chemistry
Sarah L Dombernowsky, Jeanette Schwarz, Jacob Samsøe-Petersen, Reidar Albrechtsen, Kim B Jensen, Gary Thomas, Marie Kveiborg
PACS-2 is a multifunctional sorting protein that mediates cell homeostasis. We recently identified PACS-2 in a functional genome-wide siRNA screen for novel regulators of the metalloproteinase ADAM17, the main sheddase for ligands of the ErbB receptor family. Of note, we showed that Pacs2-/- mice have significantly reduced EGFR activity and proliferative index in the intestinal epithelium. As EGFR signaling is highly mitogenic for intestinal epithelial stem cells, and plays essential roles in intestinal epithelial regeneration and tumor development, we have now examined the role of PACS-2 in these processes...
December 12, 2017: Oncotarget
Stefanie Maurer, Korbinian Nepomuk Kropp, Gerd Klein, Alexander Steinle, Sebastian P Haen, Juliane S Walz, Clemens Hinterleitner, Melanie Märklin, Hans-Georg Kopp, Helmut Rainer Salih
Platelets promote metastasis, among others by coating cancer cells traveling through the blood, which results in protection from NK cell immune-surveillance. The underlying mechanisms, however, remain to be fully elucidated. Here we report that platelet-coating reduces surface expression of NKG2D ligands, in particular MICA and MICB, on tumor cells, which was mirrored by enhanced release of their soluble ectodomains. Similar results were obtained upon exposure of tumor cells to platelet-releasate and can be attributed to the sheddases ADAM10 and ADAM17 that are detectable on the platelet surface and in releasate following activation and at higher levels on platelets of patients with metastasized lung cancer compared with healthy controls...
2018: Oncoimmunology
Alexandros Nicolaou, Bernd H Northoff, Zhen Zhao, Alexander Kohlmaier, Kristina Sass, Stefan Rose-John, Sabine Steffens, Christian Weber, Daniel Teupser, Lesca M Holdt
No abstract text is available yet for this article.
January 2018: Thrombosis and Haemostasis
Christine Sommer, Sindre Lee, Hanne Løvdal Gulseth, Jørgen Jensen, Christian A Drevon, Kåre Inge Birkeland
Context: Plasma soluble leptin receptor (sOb-R) seems protective of gestational and type 2 diabetes in observational studies, but the mechanisms are unknown. sOb-R is formed by ectodomain shedding of membrane-bound leptin receptors (Ob-R), but its associations with mRNA expression is scarcely explored. Objective: To explore associations between plasma levels of sOb-R and 1) insulin sensitivity; 2) mRNA pathways in adipose tissue and skeletal muscle; and 3) mRNA of candidate genes for sOb-R generation in adipose tissue and skeletal muscle...
December 28, 2017: Journal of Clinical Endocrinology and Metabolism
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