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, Reduces Glucocorticoid Receptor Translocation and Function1
Section of Clinical Neuropharmacology, Institute of Psychiatry (C.M.P.), London, United Kingdom SE5 8AF; and the Department of Psychiatry and Behavioral Sciences, Emory University School of Medicine, Atlanta, Georgia 30322
Address all correspondence and requests for reprints to: Andrew H. Miller, M.D., Department of Psychiatry and Behavioral Sciences, Emory University School of Medicine, 1639 Pierce Drive, Suite 4000, Atlanta, Georgia 30322. E-mail: amill02{at}emory.edu
Proinflammatory cytokines have been shown to influence the expression
and function of the glucocorticoid receptor (GR). Specifically, several
studies have found that cytokines induce a decrease in GR function, as
evidenced by reduced sensitivity to glucocorticoid effects on
functional end points. To investigate the potential mechanism(s)
involved, we examined the impact of the proinflammatory cytokine,
interleukin-1
(IL-1), on 1) GR translocation from cytoplasm to
nucleus using GR immunostaining, 2) cytosolic radioligand GR binding,
and 3) GR-mediated gene transcription in L929 cells stably transfected
with the mouse mammary tumor virus-cholamphenicol acetyltransferase
reporter gene. L929 cells were treated with IL-1 (100 and 1000 U/ml)
for 24 h in the presence or absence of dexamethasone (Dex; 10
nM to 1 µM). IL-1 inhibited Dex-induced GR
translocation and alone induced GR up-regulation. Pretreatment with
IL-1 followed by Dex treatment for 1.5 h led to about 20%
inhibition of Dex-induced GR-mediated gene transcription, whereas
coincubation of IL-1 plus Dex for 24 h inhibited Dex-induced
GR-mediated gene activity up to 42%. The latter effect was reversed by
the IL-1 receptor antagonist. These results suggest that cytokines
produced during an inflammatory response may induce GR resistance in
relevant cell types by direct effects on the GR, thereby providing an
additional pathway by which the immune system can influence the
hypothalamic-pituitary-adrenal axis.
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