Coordinating Role of RXRα in Downregulating Hepatic Detoxification during Inflammation Revealed by Fuzzy-Logic Modeling.

Roland Keller,Maria Thomas,Thomas O Joos,Marcus Klein,Wolfgang E Thasler,Andreas Dräger,Andreas Zell,Markus F Templin,Ute Metzger,Ulrich M Zanger

doi:10.1371/journal.pcbi.1004431

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.

Highlights

In a variety of acute and chronic illnesses, including bacterial or viral infection, tissue injury, many chronic diseases and most cancers, proinflammatory cytokines such as interleukin (IL) 6, interleukin 1β (IL-1β), and TNFα evoke a major reorganization of hepatic gene expression resulting in the massive synthesis of acute phase proteins such as C-reactive protein (CRP) [1]
During inflammation, circulating proinflammatory cytokines such as TNFα, IL-1ß, and IL-6, which are produced by, e.g., Kupffer cells, macrophages, or tumor cells, play important roles in hepatocellular signaling pathways and in the regulation of cellular homeostasis. These cytokines are responsible for the acute phase response (APR) but PLOS Computational Biology | DOI:10.1371/journal.pcbi
Fuzzy-Logic Modeling of Hepatocyte IL-6 Response funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript

Summary

Introduction

In a variety of acute and chronic illnesses, including bacterial or viral infection, tissue injury, many chronic diseases and most cancers, proinflammatory cytokines such as interleukin (IL) 6, IL-1β, and TNFα evoke a major reorganization of hepatic gene expression resulting in the massive synthesis of acute phase proteins such as C-reactive protein (CRP) [1]. DMET genes are regulated at the constitutive level by hepatic nuclear factors (HNF) such as HNF-1α, HNF-4α, and CCAAT-enhancer binding proteins (C/EBPs) [10,11], while inducible expression involves several ligand-activated receptors including the aryl hydrocarbon receptor (AhR), the constitutive androstane receptor (CAR), the pregnane X receptor (PXR), the peroxisome proliferatoractivated receptor-α (PPARα) and others, which function as pleiotropic sensors for a large variety of endogenous and xenobiotic compounds [12,13]. Some authors suggested coordinated mechanisms, e.g. involving the major hepatic retinoid X receptor, RXRα, which is required as a heterodimerization partner for several nuclear receptors including CAR, FXR, LXR, PPAR, PXR, and VDR [19,20]

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