IL-6 modulates sepsis-induced decreases in transcription of hepatic organic anion and bile acid transporters.

Sepsis, a lethal inflammatory syndrome, is characterized by organ system dysfunction. In the liver, we have observed decreased expression of genes encoding proteins modulating key processes. These include organic anion and bile acid transport. We hypothesized that the inflammatory mediator IL-6 modulates altered expression of several key hepatic genes in sepsis via induction of the intracellular transcription factor signal transducer and activator of transcription (Stat) 3. Sepsis was induced in IL-6 +/+ and IL-6 -/- mice, and expression of the liver-restricted genes encoding the sodium-taurocholate cotransporter (Ntcp), the multidrug resistant protein (MRP) 2 and the organic anion transporter protein (OATP), was determined. As demonstrated previously, cecal ligation and puncture decreases expression of Ntcp, MRP-2, and OATP in IL-6 +/+ mice. Transcription elongation analysis demonstrated that altered expression resulted from decreased transcription. These changes were not observed in IL-6 -/- animals. Cecal ligation and puncture increased the DNA binding activity of Stat-3 in IL-6 +/+ but not IL-6 -/- mice. Because the promoters of Ntcp, MRP-2, and OATP do not contain Stat-3 binding sites, we postulated that altered Ntcp, MRP-2, and OATP expression resulted from activation of hepatocyte nuclear factor (HNF) 1alpha, which is IL-6 dependent. Cecal ligation and puncture decreased HNF-1alpha expression and DNA binding activity in IL-6 +/+ but not IL-6 -/- mice. Recombinant human IL-6 restored the sepsis-induced decrease in Ntcp, MRP-2, OATP, and HNF-1alpha expression in IL-6 -/- mice. We conclude that sepsis decreases the expression of three key hepatic genes via a transcriptional mechanism that is IL-6, Stat-3, and HNF-1alpha dependent.