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C/EBPβ Blocks p65 Phosphorylation and Thereby NF-κB-Mediated Transcription in TNF-Tolerant Cells
| Content Provider | Scilit |
|---|---|
| Author | Zwergal, Andreas Quirling, Martina Saugel, Bernd Huth, Karin C. Sydlik, Carmen Poli, Valeria Neumeier, Dieter Ziegler-Heitbrock, H. W. Löms Brand, Korbinian |
| Copyright Year | 2006 |
| Description | TNF is a major mediator of inflammation, immunity, and apoptosis. Pre-exposure to TNF reduces sensitivity to restimulation, a phenomenon known as tolerance, considered as protective in sepsis, but also as a paradigm for immunoparalysis. Earlier experiments in TNF-tolerant cells display inhibition of NF-κB-dependent IL-8 gene expression at the transcriptional level with potential involvement of C/EBPβ. In this study, we have shown that a κB motive was sufficient to mediate transcriptional inhibition under TNF tolerance conditions in monocytic cells. Furthermore, in tolerant cells, TNF-induced NF-κB p65 phosphorylation was markedly decreased, which was accompanied by the formation of C/EBPβ-p65 complexes. Remarkably, in C/EBPβ−/− cells incubated under the conditions of TNF tolerance, neither impairment of transcription nor inhibition of p65 phosphorylation was observed. Finally, we showed that C/EBPβ overexpression reduced p65-mediated transactivation and that association of C/EBPβ with p65 specifically prevented p65 phosphorylation. Our data demonstrate that C/EBPβ is an essential signaling component for inhibition of NF-κB-mediated transcription in TNF-tolerant cells and suggest that this is caused by blockade of p65 phosphorylation. These results define a new molecular mechanism responsible for TNF tolerance in monocytic cells that may contribute to the unresponsiveness seen in patients with sepsis. |
| Ending Page | 672 |
| Page Count | 8 |
| Starting Page | 665 |
| ISSN | 00221767 |
| e-ISSN | 15506606 |
| DOI | 10.4049/jimmunol.177.1.665 |
| Journal | The Journal of Immunology |
| Issue Number | 1 |
| Volume Number | 177 |
| Language | English |
| Publisher | The American Association of Immunologists |
| Publisher Date | 2006-07-01 |
| Access Restriction | Open |
| Subject Keyword | Gene Expression C/ebpβ Tnf Tolerance P65 Phosphorylation |
| Content Type | Text |
| Resource Type | Article |
| Subject | Immunology and Allergy Immunology |