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

Abstract

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.