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Weber, M.* ; Sydlik, C.* ; Quirling, M.* ; Nothdurfter, C.* ; Zwergal, A.* ; Heiss, P.* ; Bell, S.* ; Neumeier, D.* ; Ziegler-Heitbrock, L. ; Brand, K.*

Transcriptional Inhibition of Interleukin-8 Expression in Tumor Necrosis Factor-tolerant Cells.

J. Biol. Chem. 278, 23586-23593 (2003)

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Open Access Green as soon as Postprint is submitted to ZB.

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There is some evidence that the potent cytokine tumor necrosis factor (TNF) is able to induce tolerance after repeated stimulation of cells. To investigate the molecular mechanisms mediating this phenomenon, the expression of interleukin-8 (IL-8), which is regulated by transcription factors NF-kappaB and C/EBPbeta, was monitored under TNF tolerance conditions. Pretreatment of monocytic cells for 72 h with low TNF doses inhibited TNF-induced (restimulation with a high dose) IL-8 promoter-dependent transcription as well as IL-8 production. Under these conditions neither activation of NF-kappaB nor IkappaB proteolysis was affected after TNF re-stimulation, albeit a slightly reduced IkappaB-alpha level was found in the TNF pretreated but not re-stimulated sample. Remarkably, in tolerant cells an increased binding of C/EBPbeta to its IL-8 promoter-specific DNA motif as well as an elevated association of C/EBPbeta protein with p65-containing NF-kappaB complexes was observed. Finally, overexpression of C/EBPbeta, but not p65 or Oct-1, markedly prevented TNF-induced IL-8 promoter-dependent transcription. Taken together, these data indicate that the expression of IL-8 is inhibited at the transcriptional level in TNF-tolerant cells and C/EBPbeta is involved under these conditions in mediating the negative-regulatory effects, a mechanism that may play a role in inflammatory processes such as sepsis.

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Publication type Article: Journal article

Document type Scientific Article

Corresponding Author

ISSN (print) / ISBN 0021-9258

e-ISSN 1083-351X

Journal Journal of Biological Chemistry, The

Quellenangaben Volume: 278, Issue: 26, Pages: 23586-23593

Publisher American Society for Biochemistry and Molecular Biology

Non-patent literature Publications

Reviewing status Peer reviewed

Institute(s) Institute of Lung Health and Immunity (LHI)