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Glucocorticoids inhibit IL-1beta-induced GM-CSF expression at multiple levels: roles for the ERK pathway and repression by MKP-1.
Biochem J. 2010 Mar 15; 427(1):113-24.BJ

Abstract

In the present study, IL (interleukin)-1beta increased GM-CSF (granulocyte/macrophage colony-stimulating factor) expression from pulmonary A549 cells and primary HBE (human bronchial epithelial) cells. These responses were repressed by the glucocorticoid dexamethasone, allowing the 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 effects were profoundly inhibited by dexamethasone, yet IL-1beta-induced GM-CSF mRNA and unspliced nRNA (nuclear RNA; a surrogate of transcription rate) were modestly inhibited by dexamethasone at times up to 2 h. Although 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 [MAPK (mitogen-activated protein kinase)/ERK (extracellular-signal-regulated kinase) kinase] inhibitors PD098059 and U0126. Although this indicates a role for the MEK/ERK pathway in GM-CSF translation, PD098059 subsequently destabilized GM-CSF mRNA. Dexamethasone and RU24858 both reduced IL-1beta-induced ERK phosphorylation and increased MKP-1 (MAPK phosphatase-1) expression. Inhibition of ERK phosphorylation was reproduced by MKP-1 overexpression and prevented by MKP-1-targeting siRNA (small interfering RNA). 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.

Authors+Show Affiliations

Airways Inflammation Research Group, Faculty of Medicine, University of Calgary, Calgary, Alberta, Canada T2N4N1. rnewton@ucalgary.caNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article

Language

eng

PubMed ID

20100175

Citation

Newton, Robert, et al. "Glucocorticoids Inhibit IL-1beta-induced GM-CSF Expression at Multiple Levels: Roles for the ERK Pathway and Repression By MKP-1." The Biochemical Journal, vol. 427, no. 1, 2010, pp. 113-24.
Newton R, King EM, Gong W, et al. Glucocorticoids inhibit IL-1beta-induced GM-CSF expression at multiple levels: roles for the ERK pathway and repression by MKP-1. Biochem J. 2010;427(1):113-24.
Newton, R., King, E. M., Gong, W., Rider, C. F., Staples, K. J., Holden, N. S., & Bergmann, M. W. (2010). Glucocorticoids inhibit IL-1beta-induced GM-CSF expression at multiple levels: roles for the ERK pathway and repression by MKP-1. The Biochemical Journal, 427(1), 113-24. https://doi.org/10.1042/BJ20091038
Newton R, et al. Glucocorticoids Inhibit IL-1beta-induced GM-CSF Expression at Multiple Levels: Roles for the ERK Pathway and Repression By MKP-1. Biochem J. 2010 Mar 15;427(1):113-24. PubMed PMID: 20100175.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Glucocorticoids inhibit IL-1beta-induced GM-CSF expression at multiple levels: roles for the ERK pathway and repression by MKP-1. AU - Newton,Robert, AU - King,Elizabeth M, AU - Gong,Wei, AU - Rider,Christopher F, AU - Staples,Karl J, AU - Holden,Neil S, AU - Bergmann,Martin W, Y1 - 2010/03/15/ PY - 2010/1/27/entrez PY - 2010/1/27/pubmed PY - 2010/4/16/medline SP - 113 EP - 24 JF - The Biochemical journal JO - Biochem J VL - 427 IS - 1 N2 - In the present study, IL (interleukin)-1beta increased GM-CSF (granulocyte/macrophage colony-stimulating factor) expression from pulmonary A549 cells and primary HBE (human bronchial epithelial) cells. These responses were repressed by the glucocorticoid dexamethasone, allowing the 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 effects were profoundly inhibited by dexamethasone, yet IL-1beta-induced GM-CSF mRNA and unspliced nRNA (nuclear RNA; a surrogate of transcription rate) were modestly inhibited by dexamethasone at times up to 2 h. Although 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 [MAPK (mitogen-activated protein kinase)/ERK (extracellular-signal-regulated kinase) kinase] inhibitors PD098059 and U0126. Although this indicates a role for the MEK/ERK pathway in GM-CSF translation, PD098059 subsequently destabilized GM-CSF mRNA. Dexamethasone and RU24858 both reduced IL-1beta-induced ERK phosphorylation and increased MKP-1 (MAPK phosphatase-1) expression. Inhibition of ERK phosphorylation was reproduced by MKP-1 overexpression and prevented by MKP-1-targeting siRNA (small interfering RNA). 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. SN - 1470-8728 UR - https://www.unboundmedicine.com/medline/citation/20100175/Glucocorticoids_inhibit_IL_1beta_induced_GM_CSF_expression_at_multiple_levels:_roles_for_the_ERK_pathway_and_repression_by_MKP_1_ L2 - https://portlandpress.com/biochemj/article-lookup/doi/10.1042/BJ20091038 DB - PRIME DP - Unbound Medicine ER -