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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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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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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DOI: https://doi.org/10.1038/ni910
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