title: Coordinating Role of RXRα in Downregulating Hepatic Detoxification during Inflammation Revealed by Fuzzy-Logic Modeling.
abstract: During various inflammatory processes circulating cytokines including IL-6, IL-1β, and TNFα 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 RXRα playing a central role in mediating transcriptional downregulation. Validation experiments revealed a striking similarity of RXRα gene silencing versus IL-6 induced negative gene regulation (rs = 0.79; P<0.0001). These results concur with RXRα functioning as obligatory heterodimerization partner for several nuclear receptors that regulate drug and lipid metabolism.
authors.affiliation: Center for Bioinformatics Tuebingen (ZBIT), University of Tuebingen, Tuebingen, Germany.
authors.forename: Roland
authors.initials: R
authors.lastname: Keller
authors.affiliation: Dr. Margarete Fischer Bosch-Institute of Clinical Pharmacology, Stuttgart.|University of Tuebingen, Tuebingen, Germany.
authors.forename: Marcus
authors.initials: M
authors.lastname: Klein
authors.affiliation: Dr. Margarete Fischer Bosch-Institute of Clinical Pharmacology, Stuttgart.|University of Tuebingen, Tuebingen, Germany.
authors.forename: Maria
authors.initials: M
authors.lastname: Thomas
authors.affiliation: Center for Bioinformatics Tuebingen (ZBIT), University of Tuebingen, Tuebingen, Germany.|Systems Biology Research Group, University of California, San Diego, La Jolla, California, United States of America.
authors.forename: Andreas
authors.initials: A
authors.lastname: Dräger
authors.affiliation: NMI Institute of Natural and Medical Sciences, Reutlingen, Germany.
authors.forename: Ute
authors.initials: U
authors.lastname: Metzger
authors.affiliation: NMI Institute of Natural and Medical Sciences, Reutlingen, Germany.
authors.forename: Markus F
authors.initials: MF
authors.lastname: Templin
authors.affiliation: NMI Institute of Natural and Medical Sciences, Reutlingen, Germany.
authors.forename: Thomas O
authors.initials: TO
authors.lastname: Joos
authors.affiliation: Department of General, Visceral, Transplantation, Vascular and Thoracic Surgery, Hospital of the University of Munich, Munich, Germany.
authors.forename: Wolfgang E
authors.initials: WE
authors.lastname: Thasler
authors.affiliation: Center for Bioinformatics Tuebingen (ZBIT), University of Tuebingen, Tuebingen, Germany.
authors.forename: Andreas
authors.initials: A
authors.lastname: Zell
authors.affiliation: Dr. Margarete Fischer Bosch-Institute of Clinical Pharmacology, Stuttgart.|University of Tuebingen, Tuebingen, Germany.
authors.forename: Ulrich M
authors.initials: UM
authors.lastname: Zanger
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D019295:Computational Biology; D015536:Down-Regulation; D005260:Female; D017143:Fuzzy Logic; D022781:Hepatocytes / Q000378:metabolism*; D006801:Humans; D008658:Inactivation, Metabolic / Q000502:physiology*; D007249:Inflammation / Q000378:metabolism*; D008297:Male; D008875:Middle Aged; D008954:Models, Biological; D047490:Retinoid X Receptor alpha / Q000378:metabolism*; D015398:Signal Transduction; D055815:Young Adult
chemical_list: D047490:Retinoid X Receptor alpha