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-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.

Bacterial Endotoxin Induces the Release of High Mobility Group Box 1 via the IFN-β Signaling Pathway

“…This discrepancy could be due to their different environmental settings, because although LPS induces HMGB1 release almost entirely through STAT-1 signaling in the cultured macrophages, other unknown processes such as cell necrosis (45) could also contribute to HMGB1 release in a JAK-dependent, but STAT-1-independent manner in in vivo settings. The evidence supporting the importance of JAK in LPS-induced lethality in vivo has been previously described in several reports, in which STAT-1 Ϫ/Ϫ mice are more susceptible to sepsis, compared with JAK protein tyrosine kinase family member-deficient Tyk2 Ϫ/Ϫ mice (28,29). Although we demonstrated that STAT-1 is critical in HMGB1 release, the detailed molecular mechanism of HMGB1 release via STAT-1 remains to be further characterized.…”

“…7E). In the case of survival, as previously reported (28,29), the survival rates of the STAT1 Ϫ/Ϫ mice compared with those of the B6 wild-type mice were increased only in low-dose LPS-treated group (20 mg/kg; Fig. 7F).…”

Suppressive Oligodeoxynucleotides Protect Mice from Lethal Endotoxic Shock

“…This effect was not limited to the down-regulation of IFN-␥; suppressive ODN also blocked the production of IFN-inducible protein-10, another gene regulated through the IFN-␤/STAT1 pathway (data not shown). Studies involving STAT1, STAT4, and Tyk2 knockout mice (TyK2 is a JAK that participates in the IFN-␤-and IL-12-mediated signaling cascade) demonstrate that these pathways contribute to LPS-induced endotoxic shock (26,40). Thus, interventions capable of targeting these signaling pathways should be of therapeutic benefit.…”

Differential Effects of CpG DNA on IFN-β Induction and STAT1 Activation in Murine Macrophages versus Dendritic Cells: Alternatively Activated STAT1 Negatively Regulates TLR Signaling in Macrophages

“…IFN-␤ signaling and classic STAT1 trans-activator function in macrophages contributes to LPS-mediated toxicity in vivo (55,56). CpG DNA is less toxic than LPS in vivo, and the apparently antiinflammatory actions of alternatively activated STAT1 may be protective in this context.…”