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 alpha(2)-macroglobulin (A2M) cor relate with recovery from sepsis and 2) STAT-3 activation and A2M transcrip tion reflect intrahepatic and not serum IL-6. Nonlethal sepsis was induced in rats by single puncture cecal ligation and puncture (CLP) and lethal sep sis via double-puncture C-LP. STAT-3 activation and A2M transcription were detected at 3-72 h and intrahepatic IL-6 at 24-72 h following single-punctu re 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 intra hepatic 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 corre lated with altered transcription of gluconeogenic, ketogenic, and ureagenic genes. IL-6 may have both beneficial and detrimental effects in sepsis. Fu lminant sepsis may decrease the ability of hepatocytes to respond to IL-6.