STAT1 (
signal transducer and activator of transcription 1) is a member of the JAK-STAT signaling family and plays a key role in facilitating gene transcription in response to activation of the types I and II
interferon (IFN) receptors. TYK2 is essential for type I, but not type II, IFN-induced STAT1 activation. Previous studies show that STAT1-deficient mice are resistant to
endotoxin-induced
shock. The goal of the present study was to assess the response of STAT1- and TYK2-deficient mice to
septic shock caused by cecal
ligation and
puncture (CLP). End points included survival, core temperature, organ injury, systemic
cytokine production, and bacterial clearance. Results showed that survival rates were significantly higher in STAT1 knockout (STAT1KO) mice compared with wild-type controls (80% vs. 10%). The improved survival of STAT1KO mice was associated with less
hypothermia,
metabolic acidosis,
hypoglycemia, and hepatocellular injury. Plasma
interleukin 6, MIP-2, CXCL10, and IFN-α concentrations were significantly lower in STAT1KO mice than in wild-type mice. In the absence of
antibiotic treatment, blood and lung bacterial counts were significantly lower in STAT1KO mice than in controls. However, treatment with
antibiotics ablated that difference. A survival advantage was not observed in TYK2-deficient mice compared with control. However, CLP-
induced hypothermia and systemic
interleukin 6 and CXCL10 production were significantly attenuated in TYK2-deficient mice. These results indicate that STAT1 activation is an important factor in the pathogenesis of CLP-induced
septic shock and is associated with the development of systemic
inflammation and organ injury. TYK2 activation also appears to contribute to CLP-induced
inflammation, but to a lesser extent than STAT1.