Glucocorticoids inhibit IL-1beta-induced GM-CSF expression at multiple levels: roles for the ERK pathway and repression by MKP-1

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Item Type:	Article
Title:	Glucocorticoids inhibit IL-1beta-induced GM-CSF expression at multiple levels: roles for the ERK pathway and repression by MKP-1
Creators Name:	Newton, R., King, E.M., Gong, W., Rider, C.F., Staples, K.J., Holden, N.S. and Bergmann, M.W.
Abstract:	Interleukin (IL)-1beta increased granulocyte/macrophage colony-stimulating factor (GM-CSF) expression from pulmonary A549 cells and primary human bronchial epithelial (HBE) cells. These responses were repressed by the glucocorticoid, dexamethasone, allowing use of A549 cells as a relevant model. IL-1beta induced GM-CSF release into the culture medium by 6 h and in cell lysates (cytosolic) at 2 h. These were profoundly inhibited by dexamethasone, yet IL-1beta-induced GM-CSF mRNA and unspliced nuclear RNA (a surrogate of transcription rate) were modestly inhibited by dexamethasone at times up to 2 h. While this indicates an effect on protein synthesis, actinomycin D chase experiments also indicated post-transcriptional repression by dexamethasone. Dexamethasone-dependent mRNA repression increased with time and was prevented by translational blockade. In addition, dexamethasone and the dissociated steroid, RU24858, repressed GM-CSF release in an actinomycin D sensitive manner thereby implicating glucocorticoid-induced gene expression. At 2 h, IL-1beta-induced expression of GM-CSF protein, but not mRNA, was sensitive to the MEK inhibitors, PD098059 and U0126. While this indicates a role for the MEK-ERK pathway in GM-CSF translation, PD098059 subsequently destabilised GM-CSF mRNA. Dexamethasone and RU24858 both reduced IL-1beta-induced ERK phosphorylation and increased MKP-1 expression. Inhibition of ERK phosphorylation was reproduced by MKP-1 over-expression and prevented by MKP-1 targeting siRNA. Since MKP-1 prevented GM-CSF expression, by transcriptional, post-transcriptional and translational processes, we propose that glucocorticoids induce MKP-1 expression to reduce both MEK-ERK activation and GM-CSF protein synthesis. Thus de novo gene expression, particularly of MKP-1, is involved in the repressive effects of glucocorticoids.
Keywords:	Inflammation, Corticosteroid, MAPK, Epithelial Cell, GM-CSF, DUSP1
Source:	Biochemical Journal
ISSN:	0264-6021
Publisher:	Portland Press
Volume:	427
Number:	1
Page Range:	113-124
Date:	15 March 2010
Official Publication:	https://doi.org/10.1042/BJ20091038
PubMed:	View item in PubMed

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