Soluble CD147 regulates endostatin via its effects on the activities of MMP-9 and secreted proteasome 20S
During progression of rheumatoid arthritis (RA), angiogenesis provides oxygen and nutrients for the cells’ increased metabolic demands and number. To turn on angiogenesis, pro-angiogenic factors must outweigh anti-angiogenic factors. We have previously shown that CD147/extracellular matrix metallopr...
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2024-01-01
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| Series: | Frontiers in Immunology |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fimmu.2024.1319939/full |
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| author | Maya M. Rahat Hala Sabtan Hala Sabtan Elina Simanovich Amir Haddad Amir Haddad Tal Gazitt Tal Gazitt Joy Feld Joy Feld Gleb Slobodin Gleb Slobodin Adi Kibari Adi Kibari Muna Elias Devy Zisman Devy Zisman Michal A. Rahat Michal A. Rahat |
| author_facet | Maya M. Rahat Hala Sabtan Hala Sabtan Elina Simanovich Amir Haddad Amir Haddad Tal Gazitt Tal Gazitt Joy Feld Joy Feld Gleb Slobodin Gleb Slobodin Adi Kibari Adi Kibari Muna Elias Devy Zisman Devy Zisman Michal A. Rahat Michal A. Rahat |
| author_sort | Maya M. Rahat |
| collection | DOAJ |
| description | During progression of rheumatoid arthritis (RA), angiogenesis provides oxygen and nutrients for the cells’ increased metabolic demands and number. To turn on angiogenesis, pro-angiogenic factors must outweigh anti-angiogenic factors. We have previously shown that CD147/extracellular matrix metalloproteinase inducer (EMMPRIN) can induce the expression of the pro-angiogenic factors vascular endothelial growth factor (VEGF) and matrix metallopeptidase 9 (MMP-9) in a co-culture of the human HT1080 fibrosarcoma and U937 monocytic-like cell lines. However, whether CD147 influences anti-angiogenic factors was not known. We now show that relative to single cultures, the co-culture of these cells not only enhanced pro-angiogenic factors but also decreased the anti-angiogenic factors endostatin and thrombospondin-1 (Tsp-1), generally increasing the angiogenic potential as measured by a wound assay. Using anti-CD147 antibody, CD147 small interfering RNA (siRNA), and recombinant CD147, we demonstrate that CD147 hormetically regulates the generation of endostatin but has no effect on Tsp-1. Since endostatin is cleaved from collagen XVIII (Col18A), we applied different protease inhibitors and established that MMP-9 and proteasome 20S, but not cathepsins, are responsible for endostatin generation. MMP-9 and proteasome 20S collaborate to synergistically enhance endostatin generation, and in a non-cellular system, CD147 enhanced MMP-9 activity and hormetically regulated proteasome 20S activity. Serum samples obtained from RA patients and healthy controls mostly corroborated these findings, indicating clinical relevance. Cumulatively, these findings suggest that secreted CD147 mediates a possibly allosteric effect on MMP-9 and proteasome 20S activities and can serve as a switch that turns angiogenesis on or off, depending on its ambient concentrations in the microenvironment. |
| first_indexed | 2024-03-08T12:14:10Z |
| format | Article |
| id | doaj.art-b0f36c55bf04449187ca9bf66d2ac71b |
| institution | Directory Open Access Journal |
| issn | 1664-3224 |
| language | English |
| last_indexed | 2024-03-08T12:14:10Z |
| publishDate | 2024-01-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Immunology |
| spelling | doaj.art-b0f36c55bf04449187ca9bf66d2ac71b2024-01-22T16:03:13ZengFrontiers Media S.A.Frontiers in Immunology1664-32242024-01-011510.3389/fimmu.2024.13199391319939Soluble CD147 regulates endostatin via its effects on the activities of MMP-9 and secreted proteasome 20SMaya M. Rahat0Hala Sabtan1Hala Sabtan2Elina Simanovich3Amir Haddad4Amir Haddad5Tal Gazitt6Tal Gazitt7Joy Feld8Joy Feld9Gleb Slobodin10Gleb Slobodin11Adi Kibari12Adi Kibari13Muna Elias14Devy Zisman15Devy Zisman16Michal A. Rahat17Michal A. Rahat18Immunotherapy Laboratory, Carmel Medical Center, Haifa, IsraelImmunotherapy Laboratory, Carmel Medical Center, Haifa, IsraelDepartment of Rheumatology, Carmel Medical Center, Haifa, IsraelImmunotherapy Laboratory, Carmel Medical Center, Haifa, IsraelDepartment of Rheumatology, Carmel Medical Center, Haifa, IsraelThe Rappaport Faculty of Medicine, Technion-Israel Institute of Technology, Haifa, IsraelDepartment of Rheumatology, Carmel Medical Center, Haifa, IsraelThe Rappaport Faculty of Medicine, Technion-Israel Institute of Technology, Haifa, IsraelDepartment of Rheumatology, Carmel Medical Center, Haifa, IsraelThe Rappaport Faculty of Medicine, Technion-Israel Institute of Technology, Haifa, IsraelThe Rappaport Faculty of Medicine, Technion-Israel Institute of Technology, Haifa, IsraelDepartment of Rheumatology, Bnai Zion Medical Center, Haifa, IsraelDepartment of Rheumatology, Carmel Medical Center, Haifa, IsraelThe Rappaport Faculty of Medicine, Technion-Israel Institute of Technology, Haifa, IsraelDepartment of Rheumatology, Carmel Medical Center, Haifa, IsraelDepartment of Rheumatology, Carmel Medical Center, Haifa, IsraelThe Rappaport Faculty of Medicine, Technion-Israel Institute of Technology, Haifa, IsraelImmunotherapy Laboratory, Carmel Medical Center, Haifa, IsraelThe Rappaport Faculty of Medicine, Technion-Israel Institute of Technology, Haifa, IsraelDuring progression of rheumatoid arthritis (RA), angiogenesis provides oxygen and nutrients for the cells’ increased metabolic demands and number. To turn on angiogenesis, pro-angiogenic factors must outweigh anti-angiogenic factors. We have previously shown that CD147/extracellular matrix metalloproteinase inducer (EMMPRIN) can induce the expression of the pro-angiogenic factors vascular endothelial growth factor (VEGF) and matrix metallopeptidase 9 (MMP-9) in a co-culture of the human HT1080 fibrosarcoma and U937 monocytic-like cell lines. However, whether CD147 influences anti-angiogenic factors was not known. We now show that relative to single cultures, the co-culture of these cells not only enhanced pro-angiogenic factors but also decreased the anti-angiogenic factors endostatin and thrombospondin-1 (Tsp-1), generally increasing the angiogenic potential as measured by a wound assay. Using anti-CD147 antibody, CD147 small interfering RNA (siRNA), and recombinant CD147, we demonstrate that CD147 hormetically regulates the generation of endostatin but has no effect on Tsp-1. Since endostatin is cleaved from collagen XVIII (Col18A), we applied different protease inhibitors and established that MMP-9 and proteasome 20S, but not cathepsins, are responsible for endostatin generation. MMP-9 and proteasome 20S collaborate to synergistically enhance endostatin generation, and in a non-cellular system, CD147 enhanced MMP-9 activity and hormetically regulated proteasome 20S activity. Serum samples obtained from RA patients and healthy controls mostly corroborated these findings, indicating clinical relevance. Cumulatively, these findings suggest that secreted CD147 mediates a possibly allosteric effect on MMP-9 and proteasome 20S activities and can serve as a switch that turns angiogenesis on or off, depending on its ambient concentrations in the microenvironment.https://www.frontiersin.org/articles/10.3389/fimmu.2024.1319939/fullendostatinCD147/EMMPRINMMP-9secreted proteasome 20Sfibroblasts-monocytes interactionsangiogenesis |
| spellingShingle | Maya M. Rahat Hala Sabtan Hala Sabtan Elina Simanovich Amir Haddad Amir Haddad Tal Gazitt Tal Gazitt Joy Feld Joy Feld Gleb Slobodin Gleb Slobodin Adi Kibari Adi Kibari Muna Elias Devy Zisman Devy Zisman Michal A. Rahat Michal A. Rahat Soluble CD147 regulates endostatin via its effects on the activities of MMP-9 and secreted proteasome 20S Frontiers in Immunology endostatin CD147/EMMPRIN MMP-9 secreted proteasome 20S fibroblasts-monocytes interactions angiogenesis |
| title | Soluble CD147 regulates endostatin via its effects on the activities of MMP-9 and secreted proteasome 20S |
| title_full | Soluble CD147 regulates endostatin via its effects on the activities of MMP-9 and secreted proteasome 20S |
| title_fullStr | Soluble CD147 regulates endostatin via its effects on the activities of MMP-9 and secreted proteasome 20S |
| title_full_unstemmed | Soluble CD147 regulates endostatin via its effects on the activities of MMP-9 and secreted proteasome 20S |
| title_short | Soluble CD147 regulates endostatin via its effects on the activities of MMP-9 and secreted proteasome 20S |
| title_sort | soluble cd147 regulates endostatin via its effects on the activities of mmp 9 and secreted proteasome 20s |
| topic | endostatin CD147/EMMPRIN MMP-9 secreted proteasome 20S fibroblasts-monocytes interactions angiogenesis |
| url | https://www.frontiersin.org/articles/10.3389/fimmu.2024.1319939/full |
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