Central role for type I interferons and Tyk2 in lipopolysaccharide-induced endotoxin shock.
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.
Karaghiosoff
Marina
M
Institute of Animal Breeding and Genetics, Veterinary University of Vienna, A-1210 Vienna, Austria.
Steinborn
Ralf
R
Kovarik
Pavel
P
Kriegshäuser
Gernot
G
Baccarini
Manuela
M
Donabauer
Birgit
B
Reichart
Ursula
U
Kolbe
Thomas
T
Bogdan
Christian
C
Leanderson
Tomas
T
Levy
David
D
Decker
Thomas
T
Müller
Mathias
M
D000818:Animals; D016207:Cytokines / Q000096:biosynthesis; D004268:DNA-Binding Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D005260:Female; D015870:Gene Expression; D050856:Interferon Regulatory Factor-1; D050839:Interferon Regulatory Factor-7; D007370:Interferon Type I / Q000235:genetics*; D016898:Interferon-alpha / Q000235:genetics; D016899:Interferon-beta / Q000235:genetics; D008070:Lipopolysaccharides / Q000633:toxicity; D008262:Macrophage Activation; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009569:Nitric Oxide / Q000096:biosynthesis; D010750:Phosphoproteins / Q000235:genetics; D011505:Protein-Tyrosine Kinases / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D011506:Proteins / Q000235:genetics / Q000378:metabolism*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D050794:STAT1 Transcription Factor; D012772:Shock, Septic / Q000209:etiology / Q000235:genetics / Q000276:immunology*; D053634:TYK2 Kinase; D015534:Trans-Activators / Q000172:deficiency / Q000235:genetics / Q000378:metabolism
D016207:Cytokines; D004268:DNA-Binding Proteins; D050856:Interferon Regulatory Factor-1; D050839:Interferon Regulatory Factor-7; D007370:Interferon Type I; D016898:Interferon-alpha; C494258:Irf1 protein, mouse; C494235:Irf7 protein, mouse; D008070:Lipopolysaccharides; D010750:Phosphoproteins; D011506:Proteins; D012333:RNA, Messenger; D050794:STAT1 Transcription Factor; C494080:Stat1 protein, mouse; D015534:Trans-Activators; D009569:Nitric Oxide; D016899:Interferon-beta; D011505:Protein-Tyrosine Kinases; D053634:TYK2 Kinase; C499356:Tyk2 protein, mouse