DUSP1 maintains IRF1 and leads to increased expression of IRF1-dependent genes: A mechanism promoting glucocorticoid-insensitivity [Signal Transduction]

August 22nd, 2016 by Shah, S., King, E. M., Mostafa, M. M., Altonsy, M. O., Newton, R.

Although, the mitogen-activated protein kinase (MAPK) phosphatase, DUSP1, mediates dexamethasone-induced repression of MAPKs, 14 out of 46 interleukin-1β (IL1B)-induced mRNAs were significantly enhanced by DUSP1 over-expression in pulmonary A549 cells. These include the interferon regulatory factor, IRF1, and the chemokine, CXCL10. Of these DUSP1-enhanced mRNAs, 10, including CXCL10, were IRF1-dependent. MAPK inhibitors and DUSP1 over-expression prolonged IRF1 expression by elevating transcription, and increasing IRF1 mRNA and protein stability. Conversely, DUSP1 silencing increased IL1B-induced MAPK phosphorylation, while significantly reducing IRF1 protein expression at 4h. This confirms a regulatory network, whereby DUSP1 switches off MAPKs to maintain IRF1 expression. There was no repression of IRF1 expression by dexamethasone in primary human bronchial epithelial cells, and in A549 cells IL1B-induced IRF1 protein was only modestly and transiently repressed. While dexamethasone did not repress IL1B-induced IRF1 protein expression at 4-6h, silencing of IL1B plus dexamethasone-induced DUSP1 significantly reduced IRF1 expression. IL1B-induced expression of CXCL10 was largely insensitive to dexamethasone, whereas other DUSP1-enhanced, IRF1-dependent mRNAs showed various degrees of repression. With IL1B plus dexamethasone, CXCL10 expression was also IRF1-dependent and expression was reduced by DUSP1 silencing. Thus, IL1B plus dexamethasone-induced DUSP1 maintains expression of IRF1 and the IRF1-dependent gene, CXCL10. This is supported by chromatin immunoprecipitation showing IRF1 recruitment to be essentially unaffected by dexamethasone at the CXCL10 promoter or at the promoters of more highly repressed IRF1-dependent genes. Since, IRF1-dependent genes, such as CXCL10, are central to host defence, these data may help explain the reduced effectiveness of glucocorticoids during asthma exacerbations.
  • Posted in Journal of Biological Chemistry, Publications
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