دورية أكاديمية
The Interplay of Notch Signaling and STAT3 in TLR-Activated Human Primary Monocytes.
| العنوان: | The Interplay of Notch Signaling and STAT3 in TLR-Activated Human Primary Monocytes. |
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| المؤلفون: | Hildebrand D; Centre for Infectious Diseases, Medical Microbiology and Hygiene, Heidelberg University Hospital, Heidelberg, Germany., Uhle F; Department of Anesthesiology, Heidelberg University Hospital, Heidelberg, Germany., Sahin D; Centre for Infectious Diseases, Medical Microbiology and Hygiene, Heidelberg University Hospital, Heidelberg, Germany., Krauser U; Department of Anesthesiology, Heidelberg University Hospital, Heidelberg, Germany., Weigand MA; Department of Anesthesiology, Heidelberg University Hospital, Heidelberg, Germany., Heeg K; Centre for Infectious Diseases, Medical Microbiology and Hygiene, Heidelberg University Hospital, Heidelberg, Germany. |
| المصدر: | Frontiers in cellular and infection microbiology [Front Cell Infect Microbiol] 2018 Jul 10; Vol. 8, pp. 241. Date of Electronic Publication: 2018 Jul 10 (Print Publication: 2018). |
| نوع المنشور: | Journal Article; Research Support, Non-U.S. Gov't |
| اللغة: | English |
| بيانات الدورية: | Publisher: Frontiers Media SA Country of Publication: Switzerland NLM ID: 101585359 Publication Model: eCollection Cited Medium: Internet ISSN: 2235-2988 (Electronic) Linking ISSN: 22352988 NLM ISO Abbreviation: Front Cell Infect Microbiol |
| أسماء مطبوعة: | Original Publication: Lausanne : Frontiers Media SA |
| مواضيع طبية MeSH: | Signal Transduction*, Monocytes/*immunology , Receptors, Notch/*metabolism , STAT3 Transcription Factor/*metabolism , Toll-Like Receptors/*metabolism, B7-H1 Antigen/metabolism ; Bacteria/immunology ; Calcium-Binding Proteins ; Cells, Cultured ; Humans ; Intercellular Signaling Peptides and Proteins/metabolism ; Lipopolysaccharides/immunology ; Membrane Proteins/metabolism |
| مستخلص: | The highly conserved Notch signaling pathway essentially participates in immunity through regulation of developmental processes and immune cell activity. In the adaptive immune system, the impact of the Notch cascade in T and B differentiation is well studied. In contrast, the function, and regulation of Notch signaling in the myeloid lineage during infection is poorly understood. Here we show that TLR signaling, triggered through LPS stimulation or in vitro infection with various Gram-negative and -positive bacteria, stimulates Notch receptor ligand Delta-like 1 (DLL1) expression and Notch signaling in human blood-derived monocytes. TLR activation induces DLL1 indirectly, through stimulated cytokine expression and autocrine cytokine receptor-mediated signal transducer and activator of transcription 3 (STAT3). Furthermore, we reveal a positive feedback loop between Notch signaling and Janus kinase (JAK)/STAT3 pathway during in vitro infection that involves Notch-boosted IL-6. Inhibition of Notch signaling by γ-secretase inhibitor DAPT impairs TLR4-stimulated accumulation of NF-κB subunits p65 in the nucleus and subsequently reduces LPS- and infection-mediated IL-6 production. The reduced IL-6 release correlates with a diminished STAT3 phosphorylation and reduced expression of STAT3-dependent target gene programmed death-ligand 1 (PD-L1). Corroborating recombinant soluble DLL1 and Notch activator oxaliplatin stimulate STAT3 phosphorylation and expression of immune-suppressive PD-L1. Therefore we propose a bidirectional interaction between Notch signaling and STAT3 that stabilizes activation of the transcription factor and supports STAT3-dependent remodeling of myeloid cells toward an immuno-suppressive phenotype. In summary, the study provides new insights into the complex network of Notch regulation in myeloid cells during in vitro infection. Moreover, it points to a participation of Notch in stabilizing TLR-mediated STAT3 activation and STAT3-mediated modulation of myeloid functional phenotype through induction of immune-suppressive PD-L1. |
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| فهرسة مساهمة: | Keywords: DLL1; Notch signaling; PD-L1; STAT3; TLR; infection |
| المشرفين على المادة: | 0 (B7-H1 Antigen) 0 (CD274 protein, human) 0 (Calcium-Binding Proteins) 0 (DLK1 protein, human) 0 (Intercellular Signaling Peptides and Proteins) 0 (Lipopolysaccharides) 0 (Membrane Proteins) 0 (Receptors, Notch) 0 (STAT3 Transcription Factor) 0 (STAT3 protein, human) 0 (Toll-Like Receptors) |
| تواريخ الأحداث: | Date Created: 20180726 Date Completed: 20190812 Latest Revision: 20191210 |
| رمز التحديث: | 20231215 |
| مُعرف محوري في PubMed: | PMC6048282 |
| DOI: | 10.3389/fcimb.2018.00241 |
| PMID: | 30042932 |
| قاعدة البيانات: | MEDLINE |
Full Text Finder | تدمد: | 2235-2988 |
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| DOI: | 10.3389/fcimb.2018.00241 |