PT  - JOURNAL ARTICLE
AU  - Suharsh Shah
AU  - Mahmoud Mostafa
AU  - Mohammed Altonsy
AU  - Robert Newton
TI  - Maintenance of IRF1 by MAPK inhibition: A mechanism by which DUSP1 reduces glucocorticoid inhibition of CXCL10
AID  - 10.1183/13993003.congress-2016.PA5068
DP  - 2016 Sep 01
TA  - European Respiratory Journal
PG  - PA5068
VI  - 48
IP  - suppl 60
4099  - http://erj.ersjournals.com/content/48/suppl_60/PA5068.short
4100  - http://erj.ersjournals.com/content/48/suppl_60/PA5068.full
SO  - Eur Respir J2016 Sep 01; 48
AB  - Introduction: The mitogen-activated protein kinase (MAPK) phosphatase, DUSP1, mediates glucocorticoid repression of MAPKs and inflammatory gene expression. However, MAPK inhibition enhances expression of the transcription factor, IRF1.Hypothesis: Inhibition of MAPKs is a mechanism by which anti-inflammatory glucocorticoids maintain IRF1 and downstream gene expression.Methods: Pulmonary A549 and primary human bronchial epithelial (HBE) cells were treated with IL1B (1ng/ml) and dexamethasone (1μM). Gene expression was measured by qPCR, western blotting and ELISA.Results: In A549 cells, DUSP1 over-expression reduced IL1B-induced expression of many inflammatory genes, but enhanced expression of IRF1 and the IRF1-dependent gene, CXCL10. IL1B rapidly, but transiently, induced IRF1 mRNA and protein expression. MAPK inhibition had little effect on this induction, but markedly reduced the loss of IRF1 following peak expression. This involved a failure to reduce IRF1 transcription as well as stabilisation of IRF1 mRNA and protein. Silencing of IL1B-induced DUSP1 increased MAPK activation and reduced IRF1 expression. With IL1B+dexamethasone, DUSP1 silencing not only reduced IRF1 expression, but reduced CXCL10 expression. Thus limited repression by dexamethasone of IL1B-induced IRF1 and CXCL10 expression in A549 and on IRF1 in primary HBE cells is in part explained by: 1) induction of DUSP1, 2) inhibition of MAPKs, and 3) subsequently elevated IRF1 expression.Conclusions: These data confirm a regulatory network, whereby DUSP1 switches off MAPKs to maintain IRF1 expression. In the presence of dexamethasone, this maintains IRF1 and CXCL10 expression.