IL-1β and TNFα Differentially Influence NF-κB Activity and FasL-Induced Apoptosis in Primary Murine Hepatocytes During LPS-Induced Inflammation
Macrophage-derived cytokines largely influence the behavior of hepatocytes during an inflammatory response. We previously reported that both TNFα and IL-1β, which are released by macrophages upon LPS stimulation, affect Fas ligand (FasL)-induced apoptotic signaling. Whereas TNFα preincubation leads...
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2019-02-01
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| Series: | Frontiers in Physiology |
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| Online Access: | https://www.frontiersin.org/article/10.3389/fphys.2019.00117/full |
| _version_ | 1818369000020639744 |
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| author | Julia Rex Anna Lutz Laura E. Faletti Ute Albrecht Maria Thomas Johannes G. Bode Christoph Borner Christoph Borner Christoph Borner Oliver Sawodny Irmgard Merfort Irmgard Merfort |
| author_facet | Julia Rex Anna Lutz Laura E. Faletti Ute Albrecht Maria Thomas Johannes G. Bode Christoph Borner Christoph Borner Christoph Borner Oliver Sawodny Irmgard Merfort Irmgard Merfort |
| author_sort | Julia Rex |
| collection | DOAJ |
| description | Macrophage-derived cytokines largely influence the behavior of hepatocytes during an inflammatory response. We previously reported that both TNFα and IL-1β, which are released by macrophages upon LPS stimulation, affect Fas ligand (FasL)-induced apoptotic signaling. Whereas TNFα preincubation leads to elevated levels of caspase-3 activity and cell death, pretreatment with IL-1β induces increased caspase-3 activity but keeps cells alive. We now report that IL-1β and TNFα differentially influence NF-κB activity resulting in a differential upregulation of target genes, which may contribute to the distinct effects on cell viability. A reduced NF-κB activation model was established to further investigate the molecular mechanisms which determine the distinct cell fate decisions after IL-1β and TNFα stimulation. To study this aspect in a more physiological setting, we used supernatants from LPS-stimulated bone marrow-derived macrophages (BMDMs). The treatment of hepatocytes with the BMDM supernatant, which contains both IL-1β and TNFα, sensitized to FasL-induced caspase-3 activation and cell death. However, when TNFα action was blocked by neutralizing antibodies, cell viability after stimulation with the BMDM supernatant and FasL increased as compared to single FasL stimulation. This indicates the important role of TNFα in the sensitization of apoptosis in hepatocytes. These results give first insights into the complex interplay between macrophages and hepatocytes which may influence life/death decisions of hepatocytes during an inflammatory reaction of the liver in response to a bacterial infection. |
| first_indexed | 2024-12-13T23:16:53Z |
| format | Article |
| id | doaj.art-9497fdc7c120476c9edbda1f8865aea2 |
| institution | Directory Open Access Journal |
| issn | 1664-042X |
| language | English |
| last_indexed | 2024-12-13T23:16:53Z |
| publishDate | 2019-02-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Physiology |
| spelling | doaj.art-9497fdc7c120476c9edbda1f8865aea22022-12-21T23:27:54ZengFrontiers Media S.A.Frontiers in Physiology1664-042X2019-02-011010.3389/fphys.2019.00117340776IL-1β and TNFα Differentially Influence NF-κB Activity and FasL-Induced Apoptosis in Primary Murine Hepatocytes During LPS-Induced InflammationJulia Rex0Anna Lutz1Laura E. Faletti2Ute Albrecht3Maria Thomas4Johannes G. Bode5Christoph Borner6Christoph Borner7Christoph Borner8Oliver Sawodny9Irmgard Merfort10Irmgard Merfort11Institute for System Dynamics, University of Stuttgart, Stuttgart, GermanyDepartment of Pharmaceutical Biology and Biotechnology, Albert Ludwigs University Freiburg, Freiburg, GermanyInstitute of Molecular Medicine and Cell Research, Albert Ludwigs University Freiburg, Freiburg, GermanyClinic of Gastroenterology, Hepatology and Infection Diseases, Heinrich-Heine-University, Duesseldorf, GermanyDr. Margarete Fischer-Bosch Institute of Clinical Pharmacology, Stuttgart and University of Tuebingen, Tuebingen, GermanyClinic of Gastroenterology, Hepatology and Infection Diseases, Heinrich-Heine-University, Duesseldorf, GermanyDepartment of Pharmaceutical Biology and Biotechnology, Albert Ludwigs University Freiburg, Freiburg, GermanySpemann Graduate School of Biology and Medicine, Albert Ludwigs University Freiburg, Freiburg, GermanyBIOSS Centre for Biological Signaling Studies, Albert Ludwigs University Freiburg, Freiburg, GermanyInstitute for System Dynamics, University of Stuttgart, Stuttgart, GermanyDepartment of Pharmaceutical Biology and Biotechnology, Albert Ludwigs University Freiburg, Freiburg, GermanySpemann Graduate School of Biology and Medicine, Albert Ludwigs University Freiburg, Freiburg, GermanyMacrophage-derived cytokines largely influence the behavior of hepatocytes during an inflammatory response. We previously reported that both TNFα and IL-1β, which are released by macrophages upon LPS stimulation, affect Fas ligand (FasL)-induced apoptotic signaling. Whereas TNFα preincubation leads to elevated levels of caspase-3 activity and cell death, pretreatment with IL-1β induces increased caspase-3 activity but keeps cells alive. We now report that IL-1β and TNFα differentially influence NF-κB activity resulting in a differential upregulation of target genes, which may contribute to the distinct effects on cell viability. A reduced NF-κB activation model was established to further investigate the molecular mechanisms which determine the distinct cell fate decisions after IL-1β and TNFα stimulation. To study this aspect in a more physiological setting, we used supernatants from LPS-stimulated bone marrow-derived macrophages (BMDMs). The treatment of hepatocytes with the BMDM supernatant, which contains both IL-1β and TNFα, sensitized to FasL-induced caspase-3 activation and cell death. However, when TNFα action was blocked by neutralizing antibodies, cell viability after stimulation with the BMDM supernatant and FasL increased as compared to single FasL stimulation. This indicates the important role of TNFα in the sensitization of apoptosis in hepatocytes. These results give first insights into the complex interplay between macrophages and hepatocytes which may influence life/death decisions of hepatocytes during an inflammatory reaction of the liver in response to a bacterial infection.https://www.frontiersin.org/article/10.3389/fphys.2019.00117/fullprimary murine hepatocytesmacrophagessignalingapoptosisLPS-induced inflammation |
| spellingShingle | Julia Rex Anna Lutz Laura E. Faletti Ute Albrecht Maria Thomas Johannes G. Bode Christoph Borner Christoph Borner Christoph Borner Oliver Sawodny Irmgard Merfort Irmgard Merfort IL-1β and TNFα Differentially Influence NF-κB Activity and FasL-Induced Apoptosis in Primary Murine Hepatocytes During LPS-Induced Inflammation Frontiers in Physiology primary murine hepatocytes macrophages signaling apoptosis LPS-induced inflammation |
| title | IL-1β and TNFα Differentially Influence NF-κB Activity and FasL-Induced Apoptosis in Primary Murine Hepatocytes During LPS-Induced Inflammation |
| title_full | IL-1β and TNFα Differentially Influence NF-κB Activity and FasL-Induced Apoptosis in Primary Murine Hepatocytes During LPS-Induced Inflammation |
| title_fullStr | IL-1β and TNFα Differentially Influence NF-κB Activity and FasL-Induced Apoptosis in Primary Murine Hepatocytes During LPS-Induced Inflammation |
| title_full_unstemmed | IL-1β and TNFα Differentially Influence NF-κB Activity and FasL-Induced Apoptosis in Primary Murine Hepatocytes During LPS-Induced Inflammation |
| title_short | IL-1β and TNFα Differentially Influence NF-κB Activity and FasL-Induced Apoptosis in Primary Murine Hepatocytes During LPS-Induced Inflammation |
| title_sort | il 1β and tnfα differentially influence nf κb activity and fasl induced apoptosis in primary murine hepatocytes during lps induced inflammation |
| topic | primary murine hepatocytes macrophages signaling apoptosis LPS-induced inflammation |
| url | https://www.frontiersin.org/article/10.3389/fphys.2019.00117/full |
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