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Originally published In Press as doi:10.1074/jbc.M002806200 on June 26, 2000

J. Biol. Chem., Vol. 275, Issue 38, 29587-29593, September 22, 2000
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Persistent Tumor Necrosis Factor Signaling in Normal Human Fibroblasts Prevents the Complete Resynthesis of Ikappa B-alpha *

David M. PoppersDagger , Paul Schwenger§, and Jan Vilcek

From the Department of Microbiology and Kaplan Cancer Center, New York University School of Medicine, New York, New York 10016

Transcription factor NF-kappa B is normally sequestered in the cytoplasm, complexed with Ikappa B inhibitory proteins. Tumor necrosis factor (TNF) and interleukin-1 induce Ikappa B-alpha phosphorylation, leading to Ikappa B-alpha degradation and translocation of NF-kappa B to the nucleus where it activates genes important in inflammatory and immune responses. TNF and interleukin-1 actions are typically terminated by desensitization, and Ikappa B-alpha reappearance normally occurs within 30-60 min. We found that in normal human FS-4 fibroblasts maintained in the presence of TNF, Ikappa B-alpha protein failed to return to base-line levels for up to 15 h. Removal of TNF at any time during the 15-h period resulted in complete Ikappa B-alpha resynthesis, suggesting that Ikappa B-alpha reappearance was prevented by continued TNF signaling. Long term exposure of FS-4 fibroblasts to TNF led to a persistent presence of Ikappa B-alpha mRNA, sustained Ikappa B kinase activation, continuous proteasome-mediated degradation of Ikappa B-alpha , and sustained nuclear localization of NF-kappa B. Continuous exposure of FS-4 cells to TNF did not lead to a sustained activation of p38 or ERK mitogen-activated protein kinases, suggesting that not all TNF-induced signaling pathways are persistently activated. These findings challenge the notion that all cytokine-mediated signals are rapidly terminated by desensitization and illustrate the need to elucidate the process of deactivation of TNF-induced signaling.

* This work was supported in part by National Institutes of Health Grants R01-CA75071 and R35-CA49731.The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Dagger Supported by National Institutes of Health Training Grant 5T32-GM07308 from the Medical Scientist Training Program.

§ To whom correspondence may be addressed: Dept. of Microbiology, New York University School of Medicine, 550 First Ave., New York, NY 10016. Tel.: 212-263-5315; Fax: 212-263-7933; E-mail: schwep01@med.nyu.edu.

To whom correspondence may be addressed: Dept. of Microbiology, New York University School of Medicine, 550 First Ave., New York, NY 10016. Tel.: 212-263-5315; Fax: 212-263-7933; E-mail: jan.vilcek@med.nyu.edu.

Copyright © 2000 by The American Society for Biochemistry and Molecular Biology, Inc.
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