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Blocks p65 Phosphorylation and Thereby NF-
B-Mediated Transcription in TNF-Tolerant Cells1
,¶
* Institute of Clinical Chemistry and Pathobiochemistry, Klinikum Rechts der Isar, Technische Universität München, Munich, Germany;
Department of Restorative Dentistry and Periodontology, Ludwig-Maximilians-University, Munich, Germany;
Department of Genetics, Biology, and Biochemistry, University of Turin, Turin, Italy;
Clinical Cooperation Group Inflammatory Lung Diseases, GSF-Forschungszentrum für Umwelt und Gesundheit-Institute of Inhalation Biology, Gauting, Germany; and
¶
Department of Microbiology and Immunology, University of Leicester, Leicester, United Kingdom
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-
B-dependent IL-8 gene expression at the transcriptional level with potential involvement of C/EBP
. In this study, we have shown that a B motive was sufficient to mediate transcriptional inhibition under TNF tolerance conditions in monocytic cells. Furthermore, in tolerant cells, TNF-induced NF-B p65 phosphorylation was markedly decreased, which was accompanied by the formation of C/EBP-p65 complexes. Remarkably, in C/EBP–/– cells incubated under the conditions of TNF tolerance, neither impairment of transcription nor inhibition of p65 phosphorylation was observed. Finally, we showed that C/EBP overexpression reduced p65-mediated transactivation and that association of C/EBP with p65 specifically prevented p65 phosphorylation. Our data demonstrate that C/EBP is an essential signaling component for inhibition of NF-B-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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