Glucocorticoids increase C/EBPbeta activity in the lung epithelium via phosphorylation.
Glucocorticoids are widely prescribed anti-inflammatory drugs used for the treatment of many inflammatory lung disorders. However, much still remains unknown about their molecular mechanisms of action. We have previously shown that glucocorticoid-induced transcription in the lung epithelial cell line NCI-H441 is mediated via C/EBP sites in the promoters of target genes, and is likely to involve the transcription factors C/EBPbeta and C/EBPdelta. Here, we report that C/EBPbeta is the most active C/EBP-factor in both human and mouse lung epithelium and that glucocorticoids induce DNA binding of C/EBPbeta in cultured primary mouse lung epithelial cells. Mechanistic studies in H441 cells revealed that glucocorticoids, acting via the glucocorticoid receptor, increase C/EBPbeta binding starting 10 min after stimulation. The mechanism is independent of de novo protein synthesis and involves phosphorylation of C/EBPbeta at Thr(235). Together this shows that glucocorticoids increase DNA-binding activity of C/EBPbeta via post-translational mechanism(s) involving phosphorylation.
Berg
Tove
T
Department of Medicine, Division for Respiratory Medicine, Karolinska Institute, Lung Research Laboratory, Karolinska University Hospital, Solna, Sweden.
Didon
Lukas
L
Barton
Jenny
J
Andersson
Olof
O
Nord
Magnus
M
D000818:Animals; D022782:CCAAT-Enhancer-Binding Protein-beta / Q000378:metabolism*; D002460:Cell Line; D003907:Dexamethasone / Q000008:administration & dosage*; D004305:Dose-Response Relationship, Drug; D005786:Gene Expression Regulation / Q000187:drug effects / Q000502:physiology; D005938:Glucocorticoids / Q000008:administration & dosage*; D006801:Humans; D007700:Kinetics; D008168:Lung / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D051379:Mice; D010766:Phosphorylation / Q000187:drug effects; D020545:Respiratory Mucosa / Q000187:drug effects / Q000378:metabolism*
D022782:CCAAT-Enhancer-Binding Protein-beta; D005938:Glucocorticoids; D003907:Dexamethasone