%0 Journal Article
%T Coordinating Role of RXR¦Á in Downregulating Hepatic Detoxification during Inflammation Revealed by Fuzzy-Logic Modeling
%A Roland Keller&nbsp
%A Marcus Klein&nbsp
%A Maria Thomas&nbsp
%A Andreas Dr£¿ger&nbsp
%A Ute Metzger&nbsp
%A Markus F. Templin&nbsp
%A Thomas O. Joos&nbsp
%A Wolfgang E. Thasler&nbsp
%A Andreas Zell&nbsp
%A Ulrich M. Zanger
%J PLOS Computational Biology
%D 2016
%I Public Library of Science (PLoS)
%R 10.1371/journal.pcbi.1004431
%X During various inflammatory processes circulating cytokines including IL-6, IL-1¦Â, and TNF¦Á elicit a broad and clinically relevant impairment of hepatic detoxification that is based on the simultaneous downregulation of many drug metabolizing enzymes and transporter genes. To address the question whether a common mechanism is involved we treated human primary hepatocytes with IL-6, the major mediator of the acute phase response in liver, and characterized acute phase and detoxification responses in quantitative gene expression and (phospho-)proteomics data sets. Selective inhibitors were used to disentangle the roles of JAK/STAT, MAPK, and PI3K signaling pathways. A prior knowledge-based fuzzy logic model comprising signal transduction and gene regulation was established and trained with perturbation-derived gene expression data from five hepatocyte donors. Our model suggests a greater role of MAPK/PI3K compared to JAK/STAT with the orphan nuclear receptor RXR¦Á playing a central role in mediating transcriptional downregulation. Validation experiments revealed a striking similarity of RXR¦Á gene silencing versus IL-6 induced negative gene regulation (rs = 0.79; P<0.0001). These results concur with RXR¦Á functioning as obligatory heterodimerization partner for several nuclear receptors that regulate drug and lipid metabolism.
%U http://www.ploscompbiol.org/article/info%3Adoi%2F10.1371%2Fjournal.pcbi.1004431