The role of Tyk2, Stat1 and Stat4 in LPS-induced endotoxin signals.
Mice lacking Tyk2, Stat1 or Stat4, which are members of the Jak-Stat signaling cascade, were resistant to LPS-induced endotoxin shock. Interestingly, Tyk2-deficient mice had higher resistance to LPS challenge than mice lacking either Stat1 or Stat4. The activation of MAPK and NF-kappaB by LPS, and the production of TNF-alpha and IL-12 after LPS injection, were not abrogated by the absence of Tyk2, Stat1 or Stat4. In Stat1-deficient mice, the induction of IFN-beta by LPS in macrophages was severely reduced, although the serum level of IFN-gamma was elevated after LPS injection. In contrast, in Stat-4 deficient mice, the induction of IFN-beta by LPS was normal, but the serum level of IFN-gamma remained low after LPS injection. Interestingly, the induction of both IFN-beta and IFN-gamma by LPS was severely reduced in Tyk2-deficient mice. Therefore, Stat1 and Stat4 independently play substantial roles in the susceptibility to LPS. Tyk2 is essential for LPS-induced endotoxin shock, and this signaling pathway is transduced by the activation of Stat1 and Stat4.
Kamezaki
Kenjirou
K
First Department of Internal Medicine, Faculty of Medicine, Kyushu University, Fukuoka, Japan.
Shimoda
Kazuya
K
Numata
Akihiko
A
Matsuda
Tadashi
T
Nakayama
Kei-Ichi
K
Harada
Mine
M
D000818:Animals; D016207:Cytokines / Q000097:blood; D004268:DNA-Binding Proteins / Q000172:deficiency / Q000276:immunology*; D008070:Lipopolysaccharides / Q000008:administration & dosage; D020935:MAP Kinase Signaling System / Q000187:drug effects / Q000235:genetics / Q000276:immunology*; D008262:Macrophage Activation / Q000187:drug effects / Q000235:genetics / Q000276:immunology; D008264:Macrophages / Q000276:immunology*; D051379:Mice; D018345:Mice, Knockout; D011505:Protein-Tyrosine Kinases / Q000172:deficiency / Q000276:immunology*; D050794:STAT1 Transcription Factor; D050795:STAT2 Transcription Factor; D012772:Shock, Septic / Q000097:blood / Q000139:chemically induced / Q000235:genetics / Q000276:immunology / Q000473:pathology; D053634:TYK2 Kinase; D015534:Trans-Activators / Q000172:deficiency / Q000276:immunology*
D016207:Cytokines; D004268:DNA-Binding Proteins; D008070:Lipopolysaccharides; D050794:STAT1 Transcription Factor; D050795:STAT2 Transcription Factor; C494080:Stat1 protein, mouse; D015534:Trans-Activators; D011505:Protein-Tyrosine Kinases; D053634:TYK2 Kinase; C499356:Tyk2 protein, mouse