Targeting synergetic endothelial inflammation by inhibiting NFKB and JAK-STAT pathways
Summary: Multiple systemic vascular inflammatory disorders are associated with endothelial dysfunction and elevated levels of TNFα and IFNγ. Combined TNFα and IFNγ stimulation induces synergetic hyperinflammation in endothelial cells (ECs) through the activation of the NFKB and JAK/STAT pathways. He...
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| Format: | Article |
| Language: | English |
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Elsevier
2025-09-01
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| Series: | iScience |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S2589004225015688 |
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| author | Stijn A. Groten Pieter Langerhorst Georgios Malamas Alastair Barraclough Arie J. Hoogendijk Maartje van den Biggelaar |
| author_facet | Stijn A. Groten Pieter Langerhorst Georgios Malamas Alastair Barraclough Arie J. Hoogendijk Maartje van den Biggelaar |
| author_sort | Stijn A. Groten |
| collection | DOAJ |
| description | Summary: Multiple systemic vascular inflammatory disorders are associated with endothelial dysfunction and elevated levels of TNFα and IFNγ. Combined TNFα and IFNγ stimulation induces synergetic hyperinflammation in endothelial cells (ECs) through the activation of the NFKB and JAK/STAT pathways. Here, we assess how targeting these pathways affects EC inflammation. Using mass spectrometry based proteomics, we investigate system-wide effects of TNFα- and IFNγ-stimulated Endothelial Colony Forming Cells (ECFCs) in combination with inhibitors targeting NFKB and JAK/STAT pathways. JAK1 inhibitor itacitinib blocked IFNγ-, but not TNFα-induced proteomic responses. IKK2/STAT3 inhibitor TPCA1 attenuated both responses. Most TNFα+IFNγ-induced proteins, such as pyroptosis mediators, chemokines, and Weibel-Palade Body content, were inhibited by both inhibitors, highlighting their synergetic dependency on both pathways. Imaging of Von Willebrand Factor (VWF) revealed an extracellular VWF network induced by combined stimulation, a phenotype which was reverted by both inhibitors. This study provides a preliminary basis for inhibiting endothelial inflammation in vascular inflammatory disorders. |
| format | Article |
| id | doaj-art-044d04776d5847e5a011e3c2dba9d8d3 |
| institution | Kabale University |
| issn | 2589-0042 |
| language | English |
| publishDate | 2025-09-01 |
| publisher | Elsevier |
| record_format | Article |
| series | iScience |
| spelling | doaj-art-044d04776d5847e5a011e3c2dba9d8d32025-08-20T05:07:27ZengElsevieriScience2589-00422025-09-0128911330710.1016/j.isci.2025.113307Targeting synergetic endothelial inflammation by inhibiting NFKB and JAK-STAT pathwaysStijn A. Groten0Pieter Langerhorst1Georgios Malamas2Alastair Barraclough3Arie J. Hoogendijk4Maartje van den Biggelaar5Department of Molecular Hematology, Sanquin Research, Plesmanlaan 125, 1066 CX Amsterdam, the NetherlandsDepartment of Molecular Hematology, Sanquin Research, Plesmanlaan 125, 1066 CX Amsterdam, the NetherlandsDepartment of Molecular Hematology, Sanquin Research, Plesmanlaan 125, 1066 CX Amsterdam, the NetherlandsDepartment of Molecular Hematology, Sanquin Research, Plesmanlaan 125, 1066 CX Amsterdam, the NetherlandsDepartment of Molecular Hematology, Sanquin Research, Plesmanlaan 125, 1066 CX Amsterdam, the NetherlandsDepartment of Molecular Hematology, Sanquin Research, Plesmanlaan 125, 1066 CX Amsterdam, the Netherlands; Corresponding authorSummary: Multiple systemic vascular inflammatory disorders are associated with endothelial dysfunction and elevated levels of TNFα and IFNγ. Combined TNFα and IFNγ stimulation induces synergetic hyperinflammation in endothelial cells (ECs) through the activation of the NFKB and JAK/STAT pathways. Here, we assess how targeting these pathways affects EC inflammation. Using mass spectrometry based proteomics, we investigate system-wide effects of TNFα- and IFNγ-stimulated Endothelial Colony Forming Cells (ECFCs) in combination with inhibitors targeting NFKB and JAK/STAT pathways. JAK1 inhibitor itacitinib blocked IFNγ-, but not TNFα-induced proteomic responses. IKK2/STAT3 inhibitor TPCA1 attenuated both responses. Most TNFα+IFNγ-induced proteins, such as pyroptosis mediators, chemokines, and Weibel-Palade Body content, were inhibited by both inhibitors, highlighting their synergetic dependency on both pathways. Imaging of Von Willebrand Factor (VWF) revealed an extracellular VWF network induced by combined stimulation, a phenotype which was reverted by both inhibitors. This study provides a preliminary basis for inhibiting endothelial inflammation in vascular inflammatory disorders.http://www.sciencedirect.com/science/article/pii/S2589004225015688BiochemistryCell biologyProteomics |
| spellingShingle | Stijn A. Groten Pieter Langerhorst Georgios Malamas Alastair Barraclough Arie J. Hoogendijk Maartje van den Biggelaar Targeting synergetic endothelial inflammation by inhibiting NFKB and JAK-STAT pathways iScience Biochemistry Cell biology Proteomics |
| title | Targeting synergetic endothelial inflammation by inhibiting NFKB and JAK-STAT pathways |
| title_full | Targeting synergetic endothelial inflammation by inhibiting NFKB and JAK-STAT pathways |
| title_fullStr | Targeting synergetic endothelial inflammation by inhibiting NFKB and JAK-STAT pathways |
| title_full_unstemmed | Targeting synergetic endothelial inflammation by inhibiting NFKB and JAK-STAT pathways |
| title_short | Targeting synergetic endothelial inflammation by inhibiting NFKB and JAK-STAT pathways |
| title_sort | targeting synergetic endothelial inflammation by inhibiting nfkb and jak stat pathways |
| topic | Biochemistry Cell biology Proteomics |
| url | http://www.sciencedirect.com/science/article/pii/S2589004225015688 |
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