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Zwergal, A.* ; Quirling, M.* ; Saugel, B.* ; Huth, K.C.* ; Sydlik, C.* ; Poli, V.* ; Neumeier, D.* ; Ziegler-Heitbrock, L. ; Brand, K.*

C/EBPß blocks p65 phosphorylation and thereby NF-kB-mediated transcription in TNF-tolerant cells.

J. Immunol. 177, 665-672 (2006)
DOI PMC
Open Access Green as soon as Postprint is submitted to ZB.
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-kappaB-dependent IL-8 gene expression at the transcriptional level with potential involvement of C/EBPbeta. In this study, we have shown that a kappaB motive was sufficient to mediate transcriptional inhibition under TNF tolerance conditions in monocytic cells. Furthermore, in tolerant cells, TNF-induced NF-kappaB p65 phosphorylation was markedly decreased, which was accompanied by the formation of C/EBPbeta-p65 complexes. Remarkably, in C/EBPbeta(-/-) cells incubated under the conditions of TNF tolerance, neither impairment of transcription nor inhibition of p65 phosphorylation was observed. Finally, we showed that C/EBPbeta overexpression reduced p65-mediated transactivation and that association of C/EBPbeta with p65 specifically prevented p65 phosphorylation. Our data demonstrate that C/EBPbeta is an essential signaling component for inhibition of NF-kappaB-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.
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Publication type Article: Journal article
Document type Scientific Article
ISSN (print) / ISBN 0022-1767
e-ISSN 1550-6606
Journal Journal of Immunology
Quellenangaben Volume: 177, Issue: 1, Pages: 665-672 Article Number: , Supplement: ,
Publisher American Association of Immunologists
Reviewing status Peer reviewed
Institute(s) Institute of Lung Health and Immunity (LHI)