Forced IFIT-2 expression represses LPS induced TNF-alpha expression at posttranscriptional levels

Berchtold, Susanne; Manncke, Birgit; Klenk, Juliane; Geisel, Julia; Autenrieth, Ingo B.; Bohn, Erwin

doi:10.1186/1471-2172-9-75

Cited by 47 publications

(51 citation statements)

References 36 publications

(40 reference statements)

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“…29 In addition, it has been shown that overexpression of Ifit2 in mouse macrophages (RAW264.7) modulates LPS-induced expression of TNFa, interleukin-6 (IL-6) and MIP-2. 30 These data suggest that Ifit proteins may have a function in early host response to different types of infection, which supports the possibility that they may be responsible for the Berr5 effect on CM.…”

Section: Discussionsupporting

confidence: 64%

Identification of a novel cerebral malaria susceptibility locus (Berr5) on mouse chromosome 19

et al. 2009

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Cerebral malaria (CM) is an acute, generally lethal condition characterized by high fever, seizures and coma. The genetic component to CM can be investigated in mouse models that vary in degree of susceptibility to infection with Plasmodium berghei ANKA. Using survival time to measure susceptibility in an informative F2 cross (n ¼ 257), we identified linkage to chromosome 19 (Berr5 (Berghei resistance locus 5), LOD ¼ 4.69) controlling, in part, the differential response between resistant BALB/c and susceptible C57BL/6 progenitors. BALB/c alleles convey increased survival through the cerebral phase of infection but have no quantitative effect on parasitemia during the later, anemic phase. The Berr5 locus colocalizes with three other immune loci, including Trl-4 (tuberculosis resistance), Tsiq2 (T-cell secretion of IL-4) and Eae19 (experimental allergic encephalitis 19), suggesting the possibility of a common genetic effect underlying these phenotypes. Potential positional candidates include the family of Ifit1-3 (interferon-inducible protein with tetratricopeptide repeats 1-3) and Fas.

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Section: Discussionsupporting

confidence: 64%

Identification of a novel cerebral malaria susceptibility locus (Berr5) on mouse chromosome 19

et al. 2009

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“…Previously, we demonstrated that forced overexpression of Ifit2 in RAW264.7 cells leads to an altered Tnf-a and Il-6 secretion after stimulation with LPS (22). Therefore, we hypothesized that Ifit2 may be involved in the regulation of IFN-induced amplification of TNF-a secretion.…”

Section: Resultsmentioning

confidence: 99%

“…Besides the antiviral activity, IFIT2 expression was associated with induction of apoptosis (21). Previous studies suggested that IFIT2 alters proinflammatory cytokine response and may therefore be involved in the development of septic shock (22).…”

mentioning

confidence: 97%

“…Polyclonal affinity-purified rabbit anti-IFIT1, anti-IFIT2, and anti-IFIT3 Abs (22), Abs specific for mouse b-actin (Sigma-Aldrich), pan-JNK/SAPK, phospho-JNK/SAPK (pT183/pY185), p38 and phospho-p38 (pT180/pY182) (BD Transduction Laboratories, Heidelberg, Germany), p44/p42 MAPK (Erk1/2), phospho-p44/p42 MAPK (Thr , and rabbit anti-human P386-IRF3 (IBL, Minneapolis, MN) were used for immunoblots, immunohistology, or flow cytometry. HRP-labeled rabbit antimouse and swine anti-rabbit secondary Abs (Dako, Glostrup, Denmark) were used for immunodetection with ECL.…”

Section: Reagents and Absmentioning

confidence: 99%

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IFIT2 Is an Effector Protein of Type I IFN–Mediated Amplification of Lipopolysaccharide (LPS)-Induced TNF-α Secretion and LPS-Induced Endotoxin Shock

Siegfried

Berchtold

Manncke

et al. 2013

The Journal of Immunology

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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.

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“…Moreover, without appropriate controls, it is difficult to ascertain whether the observed weak antiviral effects are specific or they reflect general deleterious effects of IFIT2 overexpression on the health of the cells. In contrast, a more convincing effect of mouse Ifit2 overexpression is on TNFα mRNA stability [13]. Pichlmair et al [3] did not observe any antiviral effects of overexpression of individual IFITs, but observed virus-specific stimulatory effects in response to their knockdowns.…”

mentioning

confidence: 93%

Crystal structure of IFIT2 (ISG54) predicts functional properties of IFITs

Sen

Fensterl

2012

Cell Res

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Forced IFIT-2 expression represses LPS induced TNF-alpha expression at posttranscriptional levels

Cited by 47 publications

References 36 publications

Identification of a novel cerebral malaria susceptibility locus (Berr5) on mouse chromosome 19

Identification of a novel cerebral malaria susceptibility locus (Berr5) on mouse chromosome 19

IFIT2 Is an Effector Protein of Type I IFN–Mediated Amplification of Lipopolysaccharide (LPS)-Induced TNF-α Secretion and LPS-Induced Endotoxin Shock

Crystal structure of IFIT2 (ISG54) predicts functional properties of IFITs

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