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

• DOI: 10.1038/ni910
• Publication Date: 2003-04-28T13:42:21Z
• Authors: Marina Karaghiosoff; Ralf Steinborn; Pavel Kovarik; Gernot Kriegshäuser; Manuela Baccarini; Birgit Donabauer; Ursula Reichart; Thomas Kolbe; Christian Bogdan; Tomas Leanderson; David Levy; Thomas Decker; Mathias Müller
• Keywords: Tyrosine kinase 2; Proinflammatory cytokine

Toll-like receptor-4 activation by lipopolysaccharide (LPS) induces the expression of interferon-beta (IFN-beta) 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-beta and IFN-alpha4 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-beta-null but not STAT1-null mice were also resistant to high dose LPS treatment. Together, these data suggest that Tyk2 and IFN-beta are essential effectors in LPS induced lethality.