@article{Keller2016a,
  author    = {Keller, Roland and Klein, Marcus and Thomas, Maria and Dr\"ager, Andreas and Metzger,
    Ute and Templin, Markus F. and Joos, Thomas O. and Thasler, Wolfgang E. and Zell, Andreas and
    Zanger, Ulrich M.},
  title     = {{Coordinating role of RXR$\alpha$ in downregulating hepatic detoxification during
    inflammation revealed by fuzzy-logic modeling}},
  journal   = {PLoS Computational Biology},
  publisher = {Public Library of Science},
  year      = {2016},
  month     = jan,
  volume    = {12},
  pages     = {e1004431},
  number    = {1},
  abstract  = {During various inflammatory processes circulating cytokines
    including IL-6, IL-1$\beta$, and TNF$\alpha$ elicit a broad and
    clinically relevant impairment of hepatic detoxification that is based on
    the downregulation of many drug metabolizing enzymes and transporters but it
    remained unclear, whether a common mechanism is involved. To address this
    question 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. The
    extensive data sets were used to calibrate a prior knowledge-based
    fuzzy-logic model comprising signal transduction and gene regulation. Our
    model suggests a major role of MAPK and PI3K signaling, with the orphan
    nuclear receptor RXR$\alpha$ playing a central role. Validation experiments
    revealed a striking similarity of RXR$\alpha$ gene silencing and IL-6
    stimulation with respect to negative gene regulation. These results concur
    with RXR$\alpha$ functioning as obligatory heterodimerization partner for
    several nuclear receptors that regulate drug and lipid metabolism.},
    doi     = {10.1371/journal.pcbi.1004431},
    url     = {https://doi.org/10.1371%2Fjournal.pcbi.1004431},
}