001) and Nkg2d+ NK cells (IL-1R1–/–: 4±0.4 vs WT: 6±1 %; P<0.01). Selleck SB203580 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 Selumetinib solubility dmso 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 上海皓元 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.