title: Suppression of inflammation and acute lung injury by Miz1 via repression of C/EBP-δ.
abstract: Inflammation is essential for host defense but can cause tissue damage and organ failure if unchecked. How the inflammation is resolved remains elusive. Here we report that the transcription factor Miz1 was required for terminating lipopolysaccharide (LPS)-induced inflammation. Genetic disruption of the Miz1 POZ domain, which is essential for the transactivation or repression activity of Miz1, resulted in hyperinflammation, lung injury and greater mortality in LPS-treated mice but a lower bacterial load and mortality in mice with Pseudomonas aeruginosa pneumonia. Loss of the Miz1 POZ domain prolonged the expression of proinflammatory cytokines. After stimulation, Miz1 was phosphorylated at Ser178, which was required for recruitment of the histone deacetylase HDAC1 to repress transcription of the gene encoding C/EBP-δ, an amplifier of inflammation. Our data provide a long-sought mechanism underlying the resolution of LPS-induced inflammation.
authors.affiliation: Division of Pulmonary and Critical Care Medicine, Feinberg School of Medicine, Northwestern University, Chicago, Illinois, USA.
authors.forename: Hanh Chi
authors.initials: HC
authors.lastname: Do-Umehara
authors.forename: Cong
authors.initials: C
authors.lastname: Chen
authors.forename: Daniela
authors.initials: D
authors.lastname: Urich
authors.forename: Liang
authors.initials: L
authors.lastname: Zhou
authors.forename: Ju
authors.initials: J
authors.lastname: Qiu
authors.forename: Samuel
authors.initials: S
authors.lastname: Jang
authors.forename: Alia
authors.initials: A
authors.lastname: Zander
authors.forename: Margaret A
authors.initials: MA
authors.lastname: Baker
authors.forename: Martin
authors.initials: M
authors.lastname: Eilers
authors.forename: Peter H S
authors.initials: PH
authors.lastname: Sporn
authors.forename: Karen M
authors.initials: KM
authors.lastname: Ridge
authors.forename: Jacob I
authors.initials: JI
authors.lastname: Sznajder
authors.forename: G R Scott
authors.initials: GR
authors.lastname: Budinger
authors.forename: Gökhan M
authors.initials: GM
authors.lastname: Mutlu
authors.forename: Anning
authors.initials: A
authors.lastname: Lin
authors.forename: Jing
authors.initials: J
authors.lastname: Liu
mesh_terms: D055371:Acute Lung Injury / Q000235:genetics / Q000276:immunology*; D000818:Animals; D051743:CCAAT-Enhancer-Binding Protein-delta / Q000378:metabolism*; D016207:Cytokines / Q000378:metabolism; D004794:Enzyme Repression / Q000235:genetics; D056284:Histone Deacetylase 1 / Q000378:metabolism; D007108:Immune Tolerance; D007249:Inflammation / Q000235:genetics; D018836:Inflammation Mediators / Q000378:metabolism; D008070:Lipopolysaccharides / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D016297:Mutagenesis, Site-Directed; D009363:Neoplasm Proteins / Q000235:genetics; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D010766:Phosphorylation; D050828:Protein Inhibitors of Activated STAT / Q000235:genetics / Q000378:metabolism*; D011552:Pseudomonas Infections / Q000235:genetics / Q000276:immunology*; D011550:Pseudomonas aeruginosa / Q000276:immunology*; D012097:Repressor Proteins / Q000235:genetics; D015533:Transcriptional Activation / Q000235:genetics; D044767:Ubiquitin-Protein Ligases
chemical_list: D016207:Cytokines; D018836:Inflammation Mediators; D008070:Lipopolysaccharides; D009363:Neoplasm Proteins; D009687:Nuclear Proteins; D050828:Protein Inhibitors of Activated STAT; D012097:Repressor Proteins; C485875:Zfp278 protein, mouse; D051743:CCAAT-Enhancer-Binding Protein-delta; C485521:Miz1 protein, mouse; D044767:Ubiquitin-Protein Ligases; D056284:Histone Deacetylase 1