Central role for type I interferons and Tyk2 in lipopolysaccharide-induced endotoxin shock

Karaghiosoff, Marina; Steinborn, Ralf; Kovarik, Pavel; Kriegshäuser, Gernot; Baccarini, Manuela; Donabauer, Birgit; Reichart, Ursula; Kolbe, Thomas; Bogdan, Christian; Leanderson, Tomas; Levy, David E.; Decker, Thomas; Müller, Mathias

doi:10.1038/ni910

Cited by 339 publications

(346 citation statements)

References 57 publications

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“…Also, macrophages expressing iNOS in vivo might differ in their signaling requirements from the types of phagocytes analyzed in vitro. In fact, in LPS-treated Tyk2 -/-mice the systemic NO release was as strong as in Tyk2 +/+ control mice [19]. Thus, in certain cell types and/or tissues the IFN- § / gdependent induction of iNOS can clearly occur in the absence of Tyk2.…”

Section: Tyk2 and Inosmentioning

confidence: 86%

“…Only very few data are available on the role of Tyk2 in the immune response in vivo. Tyk2 deficiency caused a reduced cytotoxic T cell response in mice infected with the lymphocytic choriomeningitis virus, led to an elevated viral replication in the spleens of mice infected with vaccinia virus [17], and protected the mice against fatal endotoxin shock [19].…”

Section: Figmentioning

confidence: 99%

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Control of Leishmania major in the absence of Tyk2 kinase

et al. 2004

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IL‐12 is indispensable for the control of many intracellular pathogens, but the components of the signaling pathway that are essential for its function in vivo are incompletely understood. Here, we investigated in the Leishmania major mouse model whether Tyk2 kinase is required for the generation of a protective immune response. Unlike C57BL/6 controls, Tyk2–/–mice developed severe skin lesions after infection that frequently ulcerated, but ultimately healed. NK cell cytotoxicity was absent in infected Tyk2–/– mice, even after IL‐12 pretreatment, which correlated with a STAT4 activation defect. IFN‐α / β, which was still able to activate STAT1 in Tyk2–/– NK cells, reconstituted their cytotoxic activity, but not their IL‐12responsiveness. The IL‐12‐induced production of IFN‐γ by NK cells and CD8+ T cells was strongly suppressed in Tyk2–/– mice at day 1 of infection, but partly regained during the late phase of infection. Tyk2–/– CD4+ T cells developed into Th1 cells (although in a delayed fashion) and infected Tyk2–/– mice expressed normals levels of inducible NO synthase. Thus, Tyk2 is required for the IL‐12 response of NK cells and CD8+ T cells in L. major‐infected mice, but not for the generation of Th1 cells and the ultimate control of the disease.

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Section: Tyk2 and Inosmentioning

confidence: 86%

Section: Figmentioning

confidence: 99%

Control of Leishmania major in the absence of Tyk2 kinase

et al. 2004

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“…Type I IFNs are traditionally viewed as antiviral cytokines although they have been shown to have a major role in response to bacterial infections 16,24 and lipopolysaccharide-induced shock. 25,26 Members of the type I IFN family all signal through a common IFNAR to activate a large set of IFNstimulated genes known to mediate responses to infections. We have shown previously that several type I IFNstimulated genes are upregulated in response to infection with the typhoid model of Salmonella Typhimurium in mice in vivo.…”

Section: Discussionmentioning

confidence: 99%

Impact of Usp18 and IFN signaling in Salmonella-induced typhlitis

et al. 2011

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In humans, Salmonella infection causes two major clinical diseases, typhoid fever and a self-limiting gastro-enteritidis. Salmonella transmission occurs by the fecal-oral route and the interactions between the bacteria and the digestive tract epithelium are central to the outcome of the infection. Using a mouse model of typhoid fever, we previously identified a mutation in USP18 affecting type I interferon (IFN) signaling resulting in increased susceptibility to systemic Salmonella infection. In this study, we demonstrate the effects of this mutation during the early response to Salmonella using a model of typhlitis. Mutant Usp18 mice showed a minimal inflammatory response early after Salmonella Typhimurium infection that was associated with low pathologic scores and low IFN-g production. This resulted in an increased interaction of Salmonella with the cecal epithelium and earlier systemic dissemination of the bacteria. The global transcriptional signature in the cecum of mouse during Salmonella infection showed normal expression of tissue specific genes and upregulation of type I IFN pathway in mutant mice. In control mice, there was a significant over-representation of genes involved in cellular recruitment and antibacterial activity paralleling the histopathological features. These results show the impact of USP18 in the development of Salmonella-induced typhlitis.

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“…Gene expression was measured by the comparative cycle threshold method (⌬⌬C T ) and was reported as the n-fold difference relative to the normalized expression of unstimulated samples (37). Primers and TaqMan MGB probes for ␤-actin, IFN-␣4, and IFN-␤ have been previously described (38,39) and were purchased from Applied Biosystems.…”

Section: Ifn-␣␤ Mrna Analysis By Quantitative Real-time Pcrmentioning

confidence: 99%

Type I IFN Signaling Is Crucial for Host Resistance against Different Species of Pathogenic Bacteria

Mancuso

Midiri

Biondo

et al. 2007

The Journal of Immunology

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It is known that host cells can produce type I IFNs (IFN-αβ) after exposure to conserved bacterial products, but the functional consequences of such responses on the outcome of bacterial infections are incompletely understood. We show in this study that IFN-αβ signaling is crucial for host defenses against different bacteria, including group B streptococci (GBS), pneumococci, and Escherichia coli. In response to GBS challenge, most mice lacking either the IFN-αβR or IFN-β died from unrestrained bacteremia, whereas all wild-type controls survived. The effect of IFN-αβR deficiency was marked, with mortality surpassing that seen in IFN-γR-deficient mice. Animals lacking both IFN-αβR and IFN-γR displayed additive lethality, suggesting that the two IFN types have complementary and nonredundant roles in host defenses. Increased production of IFN-αβ was detected in macrophages after exposure to GBS. Moreover, in the absence of IFN-αβ signaling, a marked reduction in macrophage production of IFN-γ, NO, and TNF-α was observed after stimulation with live bacteria or with purified LPS. Collectively, our data document a novel, fundamental function of IFN-αβ in boosting macrophage responses and host resistance against bacterial pathogens. These data may be useful to devise alternative strategies to treat bacterial infections.

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Central role for type I interferons and Tyk2 in lipopolysaccharide-induced endotoxin shock

Cited by 339 publications

References 57 publications

Control of Leishmania major in the absence of Tyk2 kinase

Control of Leishmania major in the absence of Tyk2 kinase

Impact of Usp18 and IFN signaling in Salmonella-induced typhlitis

Type I IFN Signaling Is Crucial for Host Resistance against Different Species of Pathogenic Bacteria

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