Failed interleukin-6 signal transduction in murine sepsis: attenuation of hepatic glycoprotein 130 phosphorylation.
OBJECTIVE
Sepsis impairs the activation of the interleukin (IL)-6 dependent transcription factor signal transducer and activator of transcription (STAT)-3. However, the molecular basis for depressed functionality has not been characterized. In this study, we test the hypothesis that altered signal transduction results from a change in the activation state of one or more of the components of the intracellular IL-6-linked pathway.


METHODS
Randomized prospective experimental study.


METHODS
University medical laboratory.


METHODS
Male, 6-8-week-old C57/Bl6 mice.


METHODS
Cecal ligation and single puncture (CLP) or cecal ligation and double puncture (2CLP) was used to model mild and fulminant sepsis, respectively. Sham-operated and unoperated animals served as controls. All animals were fluid resuscitated at the time of surgery and every 24 hours thereafter. Surviving animals were euthanized at 3, 6, 16, 24, 48, and 72 hours; blood samples were obtained and liver tissue was harvested.


RESULTS
Serum IL-6 levels were elevated in both CLP and 2CLP relative to controls. STAT-3 DNA binding activity and nuclear phosphorylated-STAT-3 levels were elevated in CLP but decreased abruptly 24 hours after 2CLP. This 2CLP-induced alteration was associated with attenuated phosphorylation of the key transcellular glycoprotein (gp) 130. Abundance and phosphorylation of the other key component of IL-6 signal transduction pathway, janus kinase-1, was unchanged following either CLP or 2CLP. 2CLP also did not cause disassociation of the gp130-janus kinase-1 complex.


CONCLUSIONS
Impaired gp130 phosphorylation may be responsible for IL-6 hyporesponsiveness during sepsis.
Abcejo
Arnoley S
AS
Department of Anesthesiology and Critical Care, University of Pennsylvania School of Medicine, Philadelphia, PA, USA.
Andrejko
Kenneth M
KM
Raj
Nichelle R
NR
Deutschman
Clifford S
CS