title: IFIT2 is an effector protein of type I IFN-mediated amplification of lipopolysaccharide (LPS)-induced TNF-α secretion and LPS-induced endotoxin shock.
abstract: Type I IFN signaling amplifies the secretion of LPS-induced proinflammatory cytokines such as TNF-α or IL-6 and might thus contribute to the high mortality associated with Gram-negative septic shock in humans. The underlying molecular mechanism, however, is ill defined. In this study, we report the generation of mice deficient in IFN-induced protein with tetratricopeptide repeats 2 (Ifit2) and demonstrate that Ifit2 is a critical signaling intermediate for LPS-induced septic shock. Ifit2 expression was significantly upregulated in response to LPS challenge in an IFN-α receptor- and IFN regulatory factor (Irf)9-dependent manner. Also, LPS induced secretion of IL-6 and TNF-α by bone marrow-derived macrophages (BMDMs) was significantly enhanced in the presence of Ifit2. In accordance, Ifit2-deficient mice exhibited significantly reduced serum levels of IL-6 and TNF-α and reduced mortality in an endotoxin shock model. Investigation of the underlying signal transduction events revealed that Ifit2 upregulates Irf3 phosphorylation. In the absence of Irf3, reduced Ifn-β mRNA expression and Ifit2 protein expression after LPS stimulation was found. Also, Tnf-α and Il-6 secretion but not Tnf-α and Il-6 mRNA expression levels were reduced. Thus, IFN-stimulated Ifit2 via enhanced Irf3 phosphorylation upregulates the secretion of proinflammatory cytokines. It thereby amplifies LPS-induced cytokine production and critically influences the outcome of endotoxin shock.
authors.affiliation: Interfakultäres Institut für Mikrobiologie und Infektionsmedizin, Eberhard Karl Universität Tuebingen, 72076 Tuebingen, Germany;
authors.forename: Alexandra
authors.initials: A
authors.lastname: Siegfried
authors.forename: Susanne
authors.initials: S
authors.lastname: Berchtold
authors.forename: Birgit
authors.initials: B
authors.lastname: Manncke
authors.forename: Eva
authors.initials: E
authors.lastname: Deuschle
authors.forename: Julia
authors.initials: J
authors.lastname: Reber
authors.forename: Thomas
authors.initials: T
authors.lastname: Ott
authors.forename: Michaela
authors.initials: M
authors.lastname: Weber
authors.forename: Ulrich
authors.initials: U
authors.lastname: Kalinke
authors.forename: Markus J
authors.initials: MJ
authors.lastname: Hofer
authors.forename: Bastian
authors.initials: B
authors.lastname: Hatesuer
authors.forename: Klaus
authors.initials: K
authors.lastname: Schughart
authors.forename: Valérie
authors.initials: V
authors.lastname: Gailus-Durner
authors.forename: Helmut
authors.initials: H
authors.lastname: Fuchs
authors.forename: Martin
authors.initials: M
authors.lastname: Hrabe de Angelis
authors.forename: Friedemann
authors.initials: F
authors.lastname: Weber
authors.forename: Mathias W
authors.initials: MW
authors.lastname: Hornef
authors.forename: Ingo B
authors.initials: IB
authors.lastname: Autenrieth
authors.forename: Erwin
authors.initials: E
authors.lastname: Bohn
mesh_terms: D000818:Animals; D051017:Apoptosis Regulatory Proteins; D016207:Cytokines / Q000096:biosynthesis; D004195:Disease Models, Animal; D005260:Female; D005786:Gene Expression Regulation; D007249:Inflammation / Q000276:immunology / Q000378:metabolism; D007370:Interferon Type I / Q000378:metabolism*; D008070:Lipopolysaccharides / Q000276:immunology*; D051379:Mice; D018345:Mice, Knockout; D011506:Proteins / Q000235:genetics / Q000276:immunology*; D012333:RNA, Messenger / Q000235:genetics; D016601:RNA-Binding Proteins; D012772:Shock, Septic / Q000276:immunology*; D015398:Signal Transduction; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis*
chemical_list: D051017:Apoptosis Regulatory Proteins; D016207:Cytokines; C092572:Ifit2 protein, mouse; D007370:Interferon Type I; D008070:Lipopolysaccharides; D011506:Proteins; D012333:RNA, Messenger; D016601:RNA-Binding Proteins; D014409:Tumor Necrosis Factor-alpha