title: DUSP1 Maintains IRF1 and Leads to Increased Expression of IRF1-dependent Genes: A MECHANISM PROMOTING GLUCOCORTICOID INSENSITIVITY.
abstract: Although the mitogen-activated protein kinase (MAPK) phosphatase, DUSP1, mediates dexamethasone-induced repression of MAPKs, 14 of 46 interleukin-1β (IL1B)-induced mRNAs were significantly enhanced by DUSP1 overexpression 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 overexpression 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 4 h. 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. Although dexamethasone did not repress IL1B-induced IRF1 protein expression at 4-6 h, 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 defense, these data may help explain the reduced effectiveness of glucocorticoids during asthma exacerbations.
authors.affiliation: From the Airways Inflammation Research Group, Snyder Institute for Chronic Diseases, University of Calgary, Calgary, Alberta, Canada T2N 4Z6 and.
authors.forename: Suharsh
authors.initials: S
authors.lastname: Shah
authors.affiliation: From the Airways Inflammation Research Group, Snyder Institute for Chronic Diseases, University of Calgary, Calgary, Alberta, Canada T2N 4Z6 and.
authors.forename: Elizabeth M
authors.initials: EM
authors.lastname: King
authors.affiliation: From the Airways Inflammation Research Group, Snyder Institute for Chronic Diseases, University of Calgary, Calgary, Alberta, Canada T2N 4Z6 and.
authors.forename: Mahmoud M
authors.initials: MM
authors.lastname: Mostafa
authors.affiliation: From the Airways Inflammation Research Group, Snyder Institute for Chronic Diseases, University of Calgary, Calgary, Alberta, Canada T2N 4Z6 and.|Department of Zoology, Sohag University, Sohag 825224, Egypt.
authors.forename: Mohammed O
authors.initials: MO
authors.lastname: Altonsy
authors.affiliation: From the Airways Inflammation Research Group, Snyder Institute for Chronic Diseases, University of Calgary, Calgary, Alberta, Canada T2N 4Z6 and rnewton@ucalgary.ca.
authors.forename: Robert
authors.initials: R
authors.lastname: Newton
mesh_terms: D000072283:A549 Cells; D054357:Chemokine CXCL10 / Q000096:biosynthesis* / Q000235:genetics; D003907:Dexamethasone / Q000494:pharmacology*; D004351:Drug Resistance / Q000187:drug effects* / Q000235:genetics; D054638:Dual Specificity Phosphatase 1 / Q000096:biosynthesis* / Q000235:genetics; D005786:Gene Expression Regulation / Q000187:drug effects*; D005938:Glucocorticoids / Q000494:pharmacology*; D006801:Humans; D050856:Interferon Regulatory Factor-1 / Q000096:biosynthesis* / Q000235:genetics; D053583:Interleukin-1beta / Q000235:genetics / Q000494:pharmacology
chemical_list: C114753:CXCL10 protein, human; D054357:Chemokine CXCL10; D005938:Glucocorticoids; C508585:IL1B protein, human; C494257:IRF1 protein, human; D050856:Interferon Regulatory Factor-1; D053583:Interleukin-1beta; D003907:Dexamethasone; C517019:DUSP1 protein, human; D054638:Dual Specificity Phosphatase 1
keywords: CXCL10; DUSP1; IRF1; MKP-1; glucocorticoid; glucocorticoid resistance; inflammation; innate immunity; interferon regulatory factor (IRF); mitogen-activated protein kinase (MAPK)