The role of Tyk2, Stat1 and Stat4 in LPS-induced endotoxin signals

• Published in: International immunology 2004-08, Vol.16 (8), p.1173-1179
• Main Authors: Kamezaki, Kenjirou, Shimoda, Kazuya, Numata, Akihiko, Matsuda, Tadashi, Nakayama, Kei-Ichi, Harada, Mine
• Format: Article
• Language: English
• Subjects: Animals; Cytokines - blood; DNA-Binding Proteins - deficiency; DNA-Binding Proteins - immunology; IFN; IL-12; Jak; Lipopolysaccharides - administration & dosage; Macrophage Activation - drug effects; Macrophage Activation - genetics; Macrophage Activation - immunology; Macrophages - immunology; MAP Kinase Signaling System - drug effects; MAP Kinase Signaling System - genetics; MAP Kinase Signaling System - immunology; Mice; Mice, Knockout; Protein-Tyrosine Kinases - deficiency; Protein-Tyrosine Kinases - immunology; Shock, Septic - blood; Shock, Septic - chemically induced; Shock, Septic - genetics; Shock, Septic - immunology; Shock, Septic - pathology; STAT1 Transcription Factor; STAT2 Transcription Factor; Trans-Activators - deficiency; Trans-Activators - immunology; TYK2 Kinase
• ISSN: 0953-8178; 1460-2377; 1460-2377
• DOI: 10.1093/intimm/dxh118

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-κB by LPS, and the production of TNF-α 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-β by LPS in macrophages was severely reduced, although the serum level of IFN-γ was elevated after LPS injection. In contrast, in Stat-4 deficient mice, the induction of IFN-β by LPS was normal, but the serum level of IFN-γ remained low after LPS injection. Interestingly, the induction of both IFN-β and IFN-γ 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.