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TIMP-1 is a novel ligand of Amyloid Precursor Protein and triggers a proinflammatory phenotype in human monocytes
The emerging cytokine tissue inhibitor of metalloproteinases-1 (TIMP-1) correlates with the progression of inflammatory diseases, including cancer. However, the effects of TIMP-1 on immune cell activation and underlying molecular mechanisms are largely unknown. Unbiased ligand-receptor-capture-scree...
Autores principales: | , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Rockefeller University Press
2023
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9837626/ https://www.ncbi.nlm.nih.gov/pubmed/36629908 http://dx.doi.org/10.1083/jcb.202206095 |
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author | Eckfeld, Celina Schoeps, Benjamin Häußler, Daniel Frädrich, Julian Bayerl, Felix Böttcher, Jan Philipp Knolle, Percy Heisz, Simone Prokopchuk, Olga Hauner, Hans Munkhbaatar, Enkhtsetseg Demir, Ihsan Ekin Hermann, Chris D. Krüger, Achim |
author_facet | Eckfeld, Celina Schoeps, Benjamin Häußler, Daniel Frädrich, Julian Bayerl, Felix Böttcher, Jan Philipp Knolle, Percy Heisz, Simone Prokopchuk, Olga Hauner, Hans Munkhbaatar, Enkhtsetseg Demir, Ihsan Ekin Hermann, Chris D. Krüger, Achim |
author_sort | Eckfeld, Celina |
collection | PubMed |
description | The emerging cytokine tissue inhibitor of metalloproteinases-1 (TIMP-1) correlates with the progression of inflammatory diseases, including cancer. However, the effects of TIMP-1 on immune cell activation and underlying molecular mechanisms are largely unknown. Unbiased ligand-receptor-capture-screening revealed TIMP-1-interaction with Amyloid Precursor Protein (APP) family members, namely APP and Amyloid Precursor-like Protein-2 (APLP2), which was confirmed by pull-down assays and confocal microscopy. We found that TIMP-1 triggered glucose uptake and proinflammatory cytokine expression in human monocytes. In cancer patients, TIMP-1 expression positively correlated with proinflammatory cytokine expression and processes associated with monocyte activation. In pancreatic cancer, TIMP-1 plasma levels correlated with the monocyte activation marker sCD163, and the combined use of both clinically accessible plasma proteins served as a powerful prognostic indicator. Mechanistically, TIMP-1 triggered monocyte activation by its C-terminal domain and via APP as demonstrated by in vitro interference, in silico docking, and the employment of recombinant TIMP-1 variants. Identification of TIMP-1 as a trigger of monocyte activation opens new therapeutic perspectives for inflammatory diseases. |
format | Online Article Text |
id | pubmed-9837626 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2023 |
publisher | Rockefeller University Press |
record_format | MEDLINE/PubMed |
spelling | pubmed-98376262023-07-11 TIMP-1 is a novel ligand of Amyloid Precursor Protein and triggers a proinflammatory phenotype in human monocytes Eckfeld, Celina Schoeps, Benjamin Häußler, Daniel Frädrich, Julian Bayerl, Felix Böttcher, Jan Philipp Knolle, Percy Heisz, Simone Prokopchuk, Olga Hauner, Hans Munkhbaatar, Enkhtsetseg Demir, Ihsan Ekin Hermann, Chris D. Krüger, Achim J Cell Biol Article The emerging cytokine tissue inhibitor of metalloproteinases-1 (TIMP-1) correlates with the progression of inflammatory diseases, including cancer. However, the effects of TIMP-1 on immune cell activation and underlying molecular mechanisms are largely unknown. Unbiased ligand-receptor-capture-screening revealed TIMP-1-interaction with Amyloid Precursor Protein (APP) family members, namely APP and Amyloid Precursor-like Protein-2 (APLP2), which was confirmed by pull-down assays and confocal microscopy. We found that TIMP-1 triggered glucose uptake and proinflammatory cytokine expression in human monocytes. In cancer patients, TIMP-1 expression positively correlated with proinflammatory cytokine expression and processes associated with monocyte activation. In pancreatic cancer, TIMP-1 plasma levels correlated with the monocyte activation marker sCD163, and the combined use of both clinically accessible plasma proteins served as a powerful prognostic indicator. Mechanistically, TIMP-1 triggered monocyte activation by its C-terminal domain and via APP as demonstrated by in vitro interference, in silico docking, and the employment of recombinant TIMP-1 variants. Identification of TIMP-1 as a trigger of monocyte activation opens new therapeutic perspectives for inflammatory diseases. Rockefeller University Press 2023-01-11 /pmc/articles/PMC9837626/ /pubmed/36629908 http://dx.doi.org/10.1083/jcb.202206095 Text en © 2023 Eckfeld et al. https://creativecommons.org/licenses/by-nc-sa/4.0/http://www.rupress.org/terms/This article is distributed under the terms of an Attribution–Noncommercial–Share Alike–No Mirror Sites license for the first six months after the publication date (see http://www.rupress.org/terms/). After six months it is available under a Creative Commons License (Attribution–Noncommercial–Share Alike 4.0 International license, as described at https://creativecommons.org/licenses/by-nc-sa/4.0/). |
spellingShingle | Article Eckfeld, Celina Schoeps, Benjamin Häußler, Daniel Frädrich, Julian Bayerl, Felix Böttcher, Jan Philipp Knolle, Percy Heisz, Simone Prokopchuk, Olga Hauner, Hans Munkhbaatar, Enkhtsetseg Demir, Ihsan Ekin Hermann, Chris D. Krüger, Achim TIMP-1 is a novel ligand of Amyloid Precursor Protein and triggers a proinflammatory phenotype in human monocytes |
title | TIMP-1 is a novel ligand of Amyloid Precursor Protein and triggers a proinflammatory phenotype in human monocytes |
title_full | TIMP-1 is a novel ligand of Amyloid Precursor Protein and triggers a proinflammatory phenotype in human monocytes |
title_fullStr | TIMP-1 is a novel ligand of Amyloid Precursor Protein and triggers a proinflammatory phenotype in human monocytes |
title_full_unstemmed | TIMP-1 is a novel ligand of Amyloid Precursor Protein and triggers a proinflammatory phenotype in human monocytes |
title_short | TIMP-1 is a novel ligand of Amyloid Precursor Protein and triggers a proinflammatory phenotype in human monocytes |
title_sort | timp-1 is a novel ligand of amyloid precursor protein and triggers a proinflammatory phenotype in human monocytes |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9837626/ https://www.ncbi.nlm.nih.gov/pubmed/36629908 http://dx.doi.org/10.1083/jcb.202206095 |
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