Il-6 Modulates Sepsis-Induced Decreases in Transcription of Hepatic Organic Anion and Bile Acid Transporters

Abstract

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 sodiumtaurocholate 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) 1α, which is IL-6 dependent. Cecal ligation and puncture decreased HNF-1α 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-1α 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-1α dependent.

Selective and Cytokine-Dependent Regulation of Hepatic Transporters and Bile Acid Homeostasis during Infectious Colitis in Mice

“…During live infection we observed a significant decrease in the mRNA expression of Abcc2 in C57BL/6J mice. Other inflammatory conditions have been reported to result in similar downregulation (Andrejko et al, 2008;Sharma et al, 2008;Cherrington et al, 2013). Multiple studies have indicated a role for IL-6 in the downregulation of Abcc2 (Siewert et al, 2004;Andrejko et al, 2008).…”

“…Other inflammatory conditions have been reported to result in similar downregulation (Andrejko et al, 2008;Sharma et al, 2008;Cherrington et al, 2013). Multiple studies have indicated a role for IL-6 in the downregulation of Abcc2 (Siewert et al, 2004;Andrejko et al, 2008). In the current study, the decrease in Abcc2 expression in IL-6-null mice failed to reach statistical significance, but the decrease did not appear to be meaningfully different from that seen in their WT controls.…”

“…Instead we investigated expression changes in genes involved in BA transport, synthesis, and regulation (Geier et al, 2007). Downregulation of these genes has been reported in several inflammatory models, including necrotizing enterocolitis , LPS treatment (Feingold et al, 1996), IL-6 or turpentine treatment (Siewert et al, 2004), extrahepatic cancer (Sharma et al, 2008), and cecal puncture (Andrejko et al, 2008). We observed downregulation of hepatic transporters Slc10a1 (sodium/taurocholate cotransporter, Ntcp) and Abcb11 (bile salt export pump, Bsep).…”

Differential transcriptional characteristics of small and large biliary epithelial cells derived from small and large bile ducts

“…Intrahepatic bile acid transport is among many of BEC important functions (26). We next examined the expression of hepatic bile acid transport genes, which are known target genes for HNF: ntcp (the Na ϩ -dependent taurocholate cotransport peptide for bile acid import, also known as slc10a1) is transcriptionally regulated by HNF1a (13) and HNF4a (13,16); mrp2 (the multidrug resistanceassociated protein for xeno-and endobiotics bile acid export, also known as abcc2) by HNF1a and HNF4a (20,32), and possibly by Foxa2 (7); and oatp1 (the organic anion transporter for basolateral bile acid uptake, also known as slc21a1) by HNF1a (4,27) and HNF4a (11,16). Since the above data showed that SV40LG and SV40SM cells have differential expression of Foxa2, HNF1a, and HNF4a transcription factors, we next sought to characterize the baseline expression of HNF6, Foxa2, HNF1a, and HNF4a target genes.…”

Cholestatic liver (dys)function during sepsis and other critical illnesses

“…In endotoxemic and septic animal studies and in critically ill humans, gene expression and protein levels of the basolateral uptake pump NTCP are markedly downregulated, likely due to suppression of essential transcription factors by pro-inflammatory cytokines [44][45][46]. The OATP uptake transporters are also downregulated by inflammation-induced mechanisms [45][46][47].…”