Pro-inflammatory cytokine induction of 11ß-hydroxysteroid dehydrogenase type 1 in A549 cells requires phosphorylation of C/EBPß at Thr235.
PLoS One
; 8(9): e75874, 2013.
Article
em En
| MEDLINE
| ID: mdl-24086653
ABSTRACT
11ß-hydroxysteroid dehydrogenase type 1 (11ß-HSD1) converts inert glucocorticoids into active forms, thereby increasing intracellular glucocorticoid levels, important to restrain acute inflammation. 11ß-HSD1 is induced by pro-inflammatory cytokines in a variety of cells. Here, we show 11ß-HSD1 expression in human A549 epithelial cells is increased by pro-inflammatory cytokines (IL-1α/TNFα) via the P2 promoter of the HSD11B1 gene. Inhibition of p38 MAPK attenuated the pro-inflammatory cytokine induction of mRNA encoding 11ß-HSD1 as well as that encoding C/EBPß. IL-1α/TNFα-induced phosphorylation of C/EBPß at Thr235 was also attenuated by p38 MAPK inhibition suggesting involvement of a p38 MAPK-C/EBPß pathway. siRNA-mediated knock-down of C/EBPß and NF-κB/RelA implicated both transcription factors in the IL-1α/TNFα induction of HSD11B1 mRNA. Transient transfections of HSD11B1 promoter-reporter constructs identified the proximal region of the P2 promoter of HSD11B1 as essential for this induction. IL-1α increased binding of C/EBPß to the HSD11B1 P2 promoter, but this was not observed for NF-κB/RelA, suggesting indirect regulation by NF-κB/RelA. Ectopic expression of mutant chicken C/EBPß constructs unable to undergo phosphorylation at the threonine equivalent to Thr235 attenuated the IL-1α-induction of HSD11B1, whereas mimicking constitutive phosphorylation of Thr235 (by mutation to aspartate) increased basal expression of HSD11B1 mRNA without affecting IL-1α-induced levels. These data clearly demonstrate a role for both C/EBPß and NF-κB/RelA in the pro-inflammatory cytokine induction of HSD11B1 in human epithelial cells and show that p38 MAPK-induced phosphorylation of C/EBPß at Thr235 is critical in this.
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Base de dados:
MEDLINE
Assunto principal:
Regulação da Expressão Gênica
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Citocinas
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Proteínas Estimuladoras de Ligação a CCAAT
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11-beta-Hidroxiesteroide Desidrogenases
Idioma:
En
Ano de publicação:
2013
Tipo de documento:
Article