PMID- 24014876
OWN - NLM
STAT- MEDLINE
DCOM- 20131126
LR  - 20201209
IS  - 1550-6606 (Electronic)
IS  - 0022-1767 (Linking)
VI  - 191
IP  - 7
DP  - 2013 Oct 1
TI  - IFIT2 is an effector protein of type I IFN-mediated amplification of 
      lipopolysaccharide (LPS)-induced TNF-alpha secretion and LPS-induced endotoxin shock.
PG  - 3913-21
LID - 10.4049/jimmunol.1203305 [doi]
AB  - Type I IFN signaling amplifies the secretion of LPS-induced proinflammatory 
      cytokines such as TNF-alpha 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-alpha receptor- and IFN regulatory factor (Irf)9-dependent 
      manner. Also, LPS induced secretion of IL-6 and TNF-alpha 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-alpha 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-beta mRNA expression and Ifit2 
      protein expression after LPS stimulation was found. Also, Tnf-alpha and Il-6 
      secretion but not Tnf-alpha 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.
FAU - Siegfried, Alexandra
AU  - Siegfried A
AD  - Interfakultares Institut fur Mikrobiologie und Infektionsmedizin, Eberhard Karl 
      Universitat Tuebingen, 72076 Tuebingen, Germany;
FAU - Berchtold, Susanne
AU  - Berchtold S
FAU - Manncke, Birgit
AU  - Manncke B
FAU - Deuschle, Eva
AU  - Deuschle E
FAU - Reber, Julia
AU  - Reber J
FAU - Ott, Thomas
AU  - Ott T
FAU - Weber, Michaela
AU  - Weber M
FAU - Kalinke, Ulrich
AU  - Kalinke U
FAU - Hofer, Markus J
AU  - Hofer MJ
FAU - Hatesuer, Bastian
AU  - Hatesuer B
FAU - Schughart, Klaus
AU  - Schughart K
FAU - Gailus-Durner, Valerie
AU  - Gailus-Durner V
FAU - Fuchs, Helmut
AU  - Fuchs H
FAU - Hrabe de Angelis, Martin
AU  - Hrabe de Angelis M
FAU - Weber, Friedemann
AU  - Weber F
FAU - Hornef, Mathias W
AU  - Hornef MW
FAU - Autenrieth, Ingo B
AU  - Autenrieth IB
FAU - Bohn, Erwin
AU  - Bohn E
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20130906
PL  - United States
TA  - J Immunol
JT  - Journal of immunology (Baltimore, Md. : 1950)
JID - 2985117R
RN  - 0 (Apoptosis Regulatory Proteins)
RN  - 0 (Cytokines)
RN  - 0 (Ifit2 protein, mouse)
RN  - 0 (Interferon Type I)
RN  - 0 (Lipopolysaccharides)
RN  - 0 (Proteins)
RN  - 0 (RNA, Messenger)
RN  - 0 (RNA-Binding Proteins)
RN  - 0 (Tumor Necrosis Factor-alpha)
SB  - IM
MH  - Animals
MH  - Apoptosis Regulatory Proteins
MH  - Cytokines/biosynthesis
MH  - Disease Models, Animal
MH  - Female
MH  - Gene Expression Regulation
MH  - Inflammation/immunology/metabolism
MH  - Interferon Type I/*metabolism
MH  - Lipopolysaccharides/*immunology
MH  - Mice
MH  - Mice, Knockout
MH  - Proteins/genetics/*immunology
MH  - RNA, Messenger/genetics
MH  - RNA-Binding Proteins
MH  - Shock, Septic/*immunology
MH  - Signal Transduction
MH  - Tumor Necrosis Factor-alpha/*biosynthesis
EDAT- 2013/09/10 06:00
MHDA- 2013/12/16 06:00
CRDT- 2013/09/10 06:00
PHST- 2013/09/10 06:00 [entrez]
PHST- 2013/09/10 06:00 [pubmed]
PHST- 2013/12/16 06:00 [medline]
AID - jimmunol.1203305 [pii]
AID - 10.4049/jimmunol.1203305 [doi]
PST - ppublish
SO  - J Immunol. 2013 Oct 1;191(7):3913-21. doi: 10.4049/jimmunol.1203305. Epub 2013 
      Sep 6.