PMID- 20100175
OWN - NLM
STAT- MEDLINE
DCOM- 20100415
LR  - 20220317
IS  - 1470-8728 (Electronic)
IS  - 0264-6021 (Linking)
VI  - 427
IP  - 1
DP  - 2010 Mar 15
TI  - Glucocorticoids inhibit IL-1beta-induced GM-CSF expression at multiple levels: 
      roles for the ERK pathway and repression by MKP-1.
PG  - 113-24
LID - 10.1042/BJ20091038 [doi]
AB  - 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.
FAU - Newton, Robert
AU  - Newton R
AD  - Airways Inflammation Research Group, Faculty of Medicine, University of Calgary, 
      Calgary, Alberta, Canada T2N4N1. rnewton@ucalgary.ca
FAU - King, Elizabeth M
AU  - King EM
FAU - Gong, Wei
AU  - Gong W
FAU - Rider, Christopher F
AU  - Rider CF
FAU - Staples, Karl J
AU  - Staples KJ
FAU - Holden, Neil S
AU  - Holden NS
FAU - Bergmann, Martin W
AU  - Bergmann MW
LA  - eng
PT  - Journal Article
DEP - 20100315
PL  - England
TA  - Biochem J
JT  - The Biochemical journal
JID - 2984726R
RN  - 0 (Anti-Inflammatory Agents)
RN  - 0 (Enzyme Inhibitors)
RN  - 0 (Interleukin-1beta)
RN  - 0 (Protein Synthesis Inhibitors)
RN  - 0 (RNA, Messenger)
RN  - 1CC1JFE158 (Dactinomycin)
RN  - 7S5I7G3JQL (Dexamethasone)
RN  - 83869-56-1 (Granulocyte-Macrophage Colony-Stimulating Factor)
RN  - 98600C0908 (Cycloheximide)
RN  - EC 2.7.11.24 (Extracellular Signal-Regulated MAP Kinases)
RN  - EC 3.1.3.48 (DUSP1 protein, human)
RN  - EC 3.1.3.48 (Dual Specificity Phosphatase 1)
SB  - IM
MH  - Anti-Inflammatory Agents/*pharmacology
MH  - Blotting, Western
MH  - Cells, Cultured
MH  - Cycloheximide/pharmacology
MH  - Dactinomycin/pharmacology
MH  - Dexamethasone/*pharmacology
MH  - Dual Specificity Phosphatase 1/*biosynthesis/genetics
MH  - Enzyme Inhibitors/pharmacology
MH  - Enzyme Repression
MH  - Enzyme-Linked Immunosorbent Assay
MH  - Epithelial Cells/drug effects/metabolism
MH  - Extracellular Signal-Regulated MAP Kinases/antagonists & 
      inhibitors/genetics/*metabolism
MH  - Granulocyte-Macrophage Colony-Stimulating Factor/genetics/*metabolism
MH  - Humans
MH  - Interleukin-1beta/*antagonists & inhibitors/pharmacology
MH  - Lung Neoplasms/metabolism/pathology
MH  - Phosphorylation
MH  - Protein Synthesis Inhibitors/pharmacology
MH  - RNA, Messenger/genetics/metabolism
MH  - Reverse Transcriptase Polymerase Chain Reaction
EDAT- 2010/01/27 06:00
MHDA- 2010/04/16 06:00
CRDT- 2010/01/27 06:00
PHST- 2010/01/27 06:00 [entrez]
PHST- 2010/01/27 06:00 [pubmed]
PHST- 2010/04/16 06:00 [medline]
AID - BJ20091038 [pii]
AID - 10.1042/BJ20091038 [doi]
PST - epublish
SO  - Biochem J. 2010 Mar 15;427(1):113-24. doi: 10.1042/BJ20091038.