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Department of Anesthesia, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104-4283
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
2-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.
cytokines; tumor necrosis factor-; mortality; multiple organ
dysfunction syndrome; systemic inflammatory response syndrome; 2-macroglobulin
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