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

Nature Immunology volume 4, pages 471–477 (2003)Cite this article

Abstract

Toll-like receptor-4 activation by lipopolysaccharide (LPS) induces the expression of interferon-β (IFN-β) in a MyD88-independent manner. Here we report that mice devoid of the JAK protein tyrosine kinase family member, Tyk2, were resistant to shock induced by high doses of LPS. Basal and LPS-induced expression of IFN-β and IFN-α4 mRNA in Tyk2-null macrophages were diminished. However, Tyk2-null mice showed normal systemic production of nitric oxide and proinflammatory cytokines and the in vivo response to tumor necrosis factor (TNF) was unperturbed. IFN-β–null but not STAT1-null mice were also resistant to high dose LPS treatment. Together, these data suggest that Tyk2 and IFN-β are essential effectors in LPS induced lethality.

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Figure 1: Tyk2-null mice are resistant to endotoxin shock induced by high doses of E. coli LPS.
Figure 2: Normal LPS-induced inflammatory and stress response in Tyk2-null mice.
Figure 3: Tyk2-null peritoneal macrophages (PMs) show normal MyD88-dependent TLR4 signaling.
Figure 4: Impaired IFN activation in Tyk2-null peritoneal macrophages (PMs).
Figure 5: High-dose LPS challenge of STAT1-null mice.
Figure 6: IFN-β–null mice are resistant to high-dose LPS challenge, but produce normal amounts of IFN-γ, TNF and NO.

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Acknowledgements

We thank R. Lajko, M. Deutschmann and G. Constantino for technical assistance, and C. Galanos and B. Strobl for helpful comments on the manuscript. This work was supported by Austrian Science Fund (FWF) grants P15335 (to M.K.), P14945 (to P.K.) and P15272 (to T.D.); by the German Research Foundation (grant DFG 996/3-1 to C.B.); and by the Austrian Ministry of Education Science and Culture (BM:BWK OEZBT GZ200.074/1-VI/1a/2002 to M.M.).

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Authors and Affiliations

  1. Institute of Animal Breeding and Genetics, Veterinary University of Vienna, Vienna, A-1210, Austria

    Marina Karaghiosoff, Ralf Steinborn, Birgit Donabauer & Mathias Müller

  2. Ludwig Boltzmann Institute for Immuno-, Cyto- and Molecular Genetics, Vienna, A-1210, Austria

    Ralf Steinborn & Ursula Reichart

  3. Institute of Microbiology and Genetics, Vienna Biocenter, Vienna, A-1030, Austria

    Pavel Kovarik, Manuela Baccarini & Thomas Decker

  4. ViennaLab Labordiagnostika GmbH, Vienna, A-1110, Austria

    Gernot Kriegshäuser

  5. Department of Biotechnology in Animal Production, IFA Tulln, Tulln, A-3430, Austria

    Thomas Kolbe

  6. Institute of Clinical Microbiology, Immunology and Hygiene, University of Erlangen, Erlangen, D-91054, Germany

    Christian Bogdan

  7. Department of Cell and Molecular Biology, Section of Immunology, Lund University, Lund, 22184, Sweden

    Tomas Leanderson

  8. Department of Pathology and Kaplan Comprehensive Cancer Center, New York University School of Medicine, New York, 10016, NY, USA

    David Levy

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Karaghiosoff, M., Steinborn, R., Kovarik, P. et al. Central role for type I interferons and Tyk2 in lipopolysaccharide-induced endotoxin shock. Nat Immunol 4, 471–477 (2003). https://doi.org/10.1038/ni910

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