Intrahepatic STAT-3 activation and acute phase gene expression predict outcome after CLP sepsis in the rat.
Interleukin-6 (IL-6) regulates hepatic acute phase responses by activating the transcription factor signal transducer and activator of transcription (STAT)-3. IL-6 also may modulate septic pathophysiology. We hypothesize that 1) STAT-3 activation and transcription of alpha2-macroglobulin (A2M) correlate with recovery from sepsis and 2) STAT-3 activation and A2M transcription reflect intrahepatic and not serum IL-6. Nonlethal sepsis was induced in rats by single puncture cecal ligation and puncture (CLP) and lethal sepsis via double-puncture CLP. STAT-3 activation and A2M transcription were detected at 3-72 h and intrahepatic IL-6 at 24-72 h following single-puncture CLP. All were detected only at 3-16 h following double-puncture CLP and at lower levels than following single-puncture CLP. Loss of serum and intrahepatic IL-6 activity after double-puncture CLP correlated with mortality. Neither intrahepatic nor serum IL-6 levels correlated with intrahepatic IL-6 activity. STAT-3 activation following single-puncture CLP inversely correlated with altered transcription of gluconeogenic, ketogenic, and ureagenic genes. IL-6 may have both beneficial and detrimental effects in sepsis. Fulminant sepsis may decrease the ability of hepatocytes to respond to IL-6.
Andrejko
K M
KM
Department of Anesthesia, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104-4283, USA.
Chen
J
J
Deutschman
C S
CS
D000209:Acute-Phase Proteins / Q000235:genetics*; D000818:Animals; D002432:Cecum; D002467:Cell Nucleus / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000378:metabolism / Q000502:physiology*; D004586:Electrophoresis; D005544:Forecasting; D015870:Gene Expression / Q000502:physiology*; D007150:Immunohistochemistry; D007239:Infections / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology*; D015850:Interleukin-6 / Q000097:blood; D008026:Ligation; D008099:Liver / Q000378:metabolism* / Q000503:physiopathology; D008297:Male; D011677:Punctures; D051381:Rats; D017207:Rats, Sprague-Dawley; D050796:STAT3 Transcription Factor; D015534:Trans-Activators / Q000378:metabolism / Q000502:physiology*; D014158:Transcription, Genetic / Q000502:physiology; D000511:alpha-Macroglobulins / Q000235:genetics
D000209:Acute-Phase Proteins; D004268:DNA-Binding Proteins; D015850:Interleukin-6; D050796:STAT3 Transcription Factor; C494088:Stat3 protein, rat; D015534:Trans-Activators; D000511:alpha-Macroglobulins