title: Beta Interferon Production Is Regulated by p38 Mitogen-Activated Protein Kinase in Macrophages via both MSK1/2- and Tristetraprolin-Dependent Pathways.
abstract: Autocrine or paracrine signaling by beta interferon (IFN-β) is essential for many of the responses of macrophages to pathogen-associated molecular patterns. This feedback loop contributes to pathological responses to infectious agents and is therefore tightly regulated. We demonstrate here that macrophage expression of IFN-β is negatively regulated by mitogen- and stress-activated kinases 1 and 2 (MSK1/2). Lipopolysaccharide (LPS)-induced expression of IFN-β was elevated in both MSK1/2 knockout mice and macrophages. Although MSK1 and -2 promote the expression of the anti-inflammatory cytokine interleukin 10, it did not strongly contribute to the ability of MSKs to regulate IFN-β expression. Instead, MSK1 and -2 inhibit IFN-β expression via the induction of dual-specificity phosphatase 1 (DUSP1), which dephosphorylates and inactivates the mitogen-activated protein kinases p38 and Jun N-terminal protein kinase (JNK). Prolonged LPS-induced activation of p38 and JNK, phosphorylation of downstream transcription factors, and overexpression of IFN-β mRNA and protein were similar in MSK1/2 and DUSP1 knockout macrophages. Two distinct mechanisms were implicated in the overexpression of IFN-β: first, JNK-mediated activation of c-jun, which binds to the IFN-β promoter, and second, p38-mediated inactivation of the mRNA-destabilizing factor tristetraprolin, which we show is able to target the IFN-β mRNA.
authors: MRC Protein Phosphorylation Unit, School of Life Sciences, Sir James Black Centre, University of Dundee, Dundee, United Kingdom.|Division of Cell Signaling and Immunology, School of Life Sciences, Sir James Black Centre, University of Dundee, Dundee, United Kingdom.
authors: Victoria A
authors: VA
authors: McGuire
authors: Institute of Inflammation and Ageing, College of Medical and Dental Sciences, University of Birmingham, Birmingham, United Kingdom.
authors: Dalya
authors: D
authors: Rosner
authors: MRC Protein Phosphorylation Unit, School of Life Sciences, Sir James Black Centre, University of Dundee, Dundee, United Kingdom.
authors: Olga
authors: O
authors: Ananieva
authors: Institute of Inflammation and Ageing, College of Medical and Dental Sciences, University of Birmingham, Birmingham, United Kingdom.
authors: Ewan A
authors: EA
authors: Ross
authors: MRC Protein Phosphorylation Unit, School of Life Sciences, Sir James Black Centre, University of Dundee, Dundee, United Kingdom.
authors: Suzanne E
authors: SE
authors: Elcombe
authors: MRC Protein Phosphorylation Unit, School of Life Sciences, Sir James Black Centre, University of Dundee, Dundee, United Kingdom.|Division of Cell Signaling and Immunology, School of Life Sciences, Sir James Black Centre, University of Dundee, Dundee, United Kingdom.
authors: Shaista
authors: S
authors: Naqvi
authors: MRC Protein Phosphorylation Unit, School of Life Sciences, Sir James Black Centre, University of Dundee, Dundee, United Kingdom.
authors: Mirjam M W
authors: MMW
authors: van den Bosch
authors: MRC Protein Phosphorylation Unit, School of Life Sciences, Sir James Black Centre, University of Dundee, Dundee, United Kingdom.
authors: Claire E
authors: CE
authors: Monk
authors: Division of Cell Signaling and Immunology, School of Life Sciences, Sir James Black Centre, University of Dundee, Dundee, United Kingdom.
authors: Tamara
authors: T
authors: Ruiz-Zorrilla Diez
authors: Institute of Inflammation and Ageing, College of Medical and Dental Sciences, University of Birmingham, Birmingham, United Kingdom.
authors: Andrew R
authors: AR
authors: Clark
authors: MRC Protein Phosphorylation Unit, School of Life Sciences, Sir James Black Centre, University of Dundee, Dundee, United Kingdom j.s.c.arthur@dundee.ac.uk.|Division of Cell Signaling and Immunology, School of Life Sciences, Sir James Black Centre, University of Dundee, Dundee, United Kingdom.
authors: J Simon C
authors: JSC
authors: Arthur
mesh_terms: D000818:Animals; D002450:Cell Communication; D002478:Cells, Cultured; D005786:Gene Expression Regulation / Q000187:drug effects; D016899:Interferon-beta / Q000378:metabolism*; D016753:Interleukin-10 / Q000378:metabolism; D008070:Lipopolysaccharides / Q000494:pharmacology; D008264:Macrophages / Q000187:drug effects / Q000276:immunology / Q000378:metabolism*; D051379:Mice; D010766:Phosphorylation; D038744:Ribosomal Protein S6 Kinases, 90-kDa / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D051816:Tristetraprolin / Q000378:metabolism*; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism*
chemical_list: C556062:IL10 protein, mouse; D008070:Lipopolysaccharides; D051816:Tristetraprolin; D016753:Interleukin-10; D016899:Interferon-beta; D038744:Ribosomal Protein S6 Kinases, 90-kDa; C485459:Rps6ka4 protein, mouse; C116919:mitogen and stress-activated protein kinase 1; D048051:p38 Mitogen-Activated Protein Kinases
keywords: CREB; DUSP1; MSK1; MSK2; TTP; beta interferon; p38 kinases