001) and Nkg2d+ NK cells (IL-1R1–/–: 4±0.4 vs WT: 6±1 %; P<0.01). DNA Damage inhibitor Conclusions: Disruption of the inflammasome by the loss of IL-1R1 signaling suppressed the activation of DCs and their ability to activate NK cells, and prevented obstruction of bile ducts in experimental biliary atresia. These data identify a regulatory role of IL-1R1 in pathogenesis of bile duct injury, and

as a potential novel therapeutic approach to treat the disease. Disclosures: Jorge A. Bezerra – Grant/Research Support: Molecular Genetics Laboratory, CHMC The following people have nothing to disclose: Tatsuki Mizuochi, Pranavkumar Shivakumar, Reena Mourya, Stephanie Walters, Bryan Donnelly, Shiva K. Shan-mukhappa Background: Hepatic macrophage activation by endotoxin (LPS) absorbed from injured intestine promotes Parenteral Nutrition Associated Cholestasis (PNAC) in mice (Hepatol-ogy. 2012;55:1518-28). Furthermore, intestinal microbiota and TLR4 signaling promote transcriptional suppression of hepatic bile salt export pump Abcb11/BSEP, bilirubin exporter Abcc2/MRP2 and sterol exporter Abcg5/8, which is associated with accumulation of cholestatic PN-derived phytosterols (Sci. Transl. Med. 2013 Oct 9;5(206):206ra137). However, the signaling pathways regulating these alterations in http://www.selleckchem.com/products/Bortezomib.html gene expression

in mice with PNAC remain undefined. The aim of this study was to elucidate the role of cytokine signaling pathways as mediators in PNAC. Methods and Results: Wild type (WT) C57/B6 mice that were exposed to dextran sulfate sodium (DSS) (to induce intestinal injury) for 4 days followed by infusion of phytosterol-containing (soy lipid) PN solution through a central venous catheter for 14 days (DSS-PN mice) developed cholestasis (increased serum bile acids and bili-rubin) and hepatocyte injury (increased AST and ALT) compared to controls (including mice treated MCE公司 with DSS only, PN only, or untreated chow fed). Compared to controls, DSS-PN mice displayed significantly reduced hepatic

mRNA amounts of Abcb11, Abcc2, Abcg5/8, paralleled by increased mRNA for Il1b while mRNA for Tnfα and Il6 were not increased. To further elucidate the role of IL-1β signaling in these pathways, mice with genetic deletion of the receptor for IL-1 (IL-1Rko) and syngeneic wild type mice were exposed to DSS-PN for 14 days or control treatments. Compared to DSS-PN wild type mice, DSS-PN treated IL-1Rko mice had significantly reduced serum AST, ALT, bile acids, and bilirubin. Moreover, hepatic gene expression of Abcb11, Abcc2, and Abcg5/8 was not reduced in DSS-PN IL1R-ko mice. To determine if IL-1β had a direct effect on hepatocytes, wild type mice were injected with recombinant IL-1β and sampled after 4 hrs, and HuH7 and HepG2 cells (human hepatocyte cell lines) were incubated with IL-1β for 4 hrs and gene expression was measured.