| Title | Inhibition of NF-{kappa}B-dependent transcription by MKP-1: Transcriptional repression by glucocorticoids occurring via p38 MAPK. | | Author(s) | King EM, Holden NS, Gong W, Rider CF, Newton R | | Institution | University of Calgary, Canada. | | Source | J Biol Chem 2009 Jul 31. | | Abstract | Acting via the glucocorticoid receptor (GR), glucocorticoids exert potent anti-inflammatory effects partly by repressing inflammatory gene transcription occurring via factors such as NF-kappaB. In the present study, the synthetic glucocorticoid, dexamethasone, induces expression of mitogen-activated protein kinase (MAPK) phosphatase (MKP)-1 in human bronchial epithelial, BEAS-2B, and pulmonary, A549, cells. This correlates with reduced TNFalpha-stimulated p38 MAPK phosphorylation. Since NF-kappaB-dependent transcription and IL-8 protein, mRNA and unspliced RNA (a surrogate of transcription rate) are sensitive to p38 MAPK inhibitors (SB203580 and SB239063), we explored the role of MKP-1 in repression of these outputs. Repression of TNFalpha-induced p38 MAPK phosphorylation, NF-kappaB-dependent transcription and IL-8 expression by dexamethasone are sensitive to transcriptional or translational inhibitors. This indicates a role for de novo gene synthesis. Adenoviral expression of MKP-1 profoundly reduces p38 MAPK phosphorylation and IL-8 expression. Similarly, NF-kappaB-dependent transcription is significantly reduced to levels consistent with maximal p38 MAPK inhibition. Thus MKP-1 attenuates TNFalpha-dependent activation of p38 MAPK, induction of IL-8 expression and NF-kappaB-dependent transcription. siRNA knockdown of dexamethasone-induced MKP-1 expression partially reverses the repression of TNFalpha-activated p38 MAPK demonstrating that MKP-1 participates in the dexamethasone-dependent repression of this pathway. In the presence of MAPK kinase (MKK) 6, a p38 MAPK activator, dexamethasone dramatically represses TNFalpha-induced NF-kappaB-dependent transcription and this is significantly reversed by MKP-1-targeting siRNA. This reveals an important and novel role for transcriptional activation (transactivation) of MKP-1 in the repression of NF-kappaB-dependent transcription by glucocorticoids. We conclude that GR transactivation is essential to the anti-inflammatory properties of GR ligands. | | Language | ENG | | Pub Type(s) | JOURNAL ARTICLE
| | PubMed ID | 19648110 |
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