title: STAT1-deficient mice are resistant to cecal ligation and puncture-induced septic shock.
abstract: 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.
authors: Department of Anesthesiology, The University of Texas Medical Branch and Shriners Hospital for Children, Galveston, Texas, USA.
authors: Daniela
authors: D
authors: Herzig
authors: Geping
authors: G
authors: Fang
authors: Tracy E
authors: TE
authors: Toliver-Kinsky
authors: Yin
authors: Y
authors: Guo
authors: Julia
authors: J
authors: Bohannon
authors: Edward R
authors: ER
authors: Sherwood
mesh_terms: D000818:Animals; D000900:Anti-Bacterial Agents / Q000494:pharmacology; D016470:Bacteremia / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D002432:Cecum; D016207:Cytokines / Q000097:blood; D004195:Disease Models, Animal; D007035:Hypothermia / Q000235:genetics / Q000378:metabolism; D007249:Inflammation / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D008026:Ligation; D051379:Mice; D018345:Mice, Knockout; D050794:STAT1 Transcription Factor / Q000235:genetics / Q000378:metabolism*; D012772:Shock, Septic / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D053634:TYK2 Kinase / Q000235:genetics / Q000378:metabolism
chemical_list: D000900:Anti-Bacterial Agents; D016207:Cytokines; D050794:STAT1 Transcription Factor; C494080:Stat1 protein, mouse; D053634:TYK2 Kinase; C499356:Tyk2 protein, mouse