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Published online 4 September 2000. doi:10.1083/jcb.150.5.1199
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© The Rockefeller University Press, 0021-9525/2000//1199 $5.00
The Journal of Cell Biology, Volume 150, Number 5, , 2000 1199-1208

Report

Glucocorticoids Antagonize Ap-1 by Inhibiting the Activation/Phosphorylation of Jnk without Affecting Its Subcellular Distribution



María Victoria Gonzáleza, Benilde Jiméneza, María T. Bercianob, José Manuel González-Sanchoa, Carme Caellesc, Miguel Lafargab, and Alberto Muñoza

a Instituto de Investigaciones Biomédicas Alberto Sols, Consejo Superior de Investigaciones Científicas-Universidad Autónoma de Madrid, E-28029 Madrid, Spain
b Departamento de Anatomía y Biología Celular, Universidad de Cantabria, E-39011 Santander, Spain
c Facultad de Farmacia, Universidad de Barcelona, E-08028, Barcelona, Spain
Instituto de Investigaciones Biomédicas Alberto Sols, Consejo Superior de Investigaciones Científicas-Universidad Autónoma de Madrid, Arturo Duperier 4, E-28029 Madrid, Spain.+34 91-5854587+34 91-5854640

amunoz{at}iib.uam.es

The immunosuppressive and antiinflammatory actions of glucocorticoid hormones are mediated by their transrepression of activating protein-1 (AP-1) and nuclear factor-kappa B (NF{kappa}B) transcription factors. Inhibition of the c-Jun NH2-terminal kinase (JNK) signaling pathway, the main mediator of AP-1 activation, has been described in extracts of hormone-treated cells. Here, we show by confocal laser microscopy, enzymatic assays, and immunoblotting that the synthetic glucocorticoid dexamethasone inhibited tumor necrosis factor {alpha} (TNF-{alpha})–induced phosphorylation and activation of JNK in the cytoplasm and nucleus of intact HeLa cells. As a result, c-Jun NH2-terminal domain phosphorylation and induction were impaired. Dexamethasone did not block the TNF-{alpha}–induced JNK nuclear translocation, but rather induced, per se, nuclear accumulation of the enzyme. Consistently with previous findings, a glucocorticoid receptor mutant (GRdim), which is deficient in dimerization, DNA binding, and transactivation, but retains AP-1 transrepressing activity, was as efficient as wild-type GR in mediating the same effects of dexamethasone on JNK in transfected Cos-7 cells. Our results show that glucocorticoids antagonize the TNF-{alpha}–induced activation of AP-1 by causing the accumulation of inactive JNK without affecting its subcellular distribution.

Key Words: dexamethasone • activating protein-1 • tumor necrosis factor {alpha} • c-Jun NH2-terminal kinase • nuclear translocation

© 2000 The Rockefeller University Press

María Victoria González and Benilde Jiménez contributed equally to this work.

Abbreviations used in this paper: AP-1, activating protein-1; Dex, dexamethasone; GR, glucocorticoid receptor; GRdim, GR mutant deficient in dimerization; GRwt, GR wild-type; Hsp70, heat shock protein 70; JNK, c-Jun NH2-terminal kinase; TNF-{alpha}, tumor necrosis factor-{alpha}.


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