Pioglitazone-mediated peroxisome proliferator-activated receptor γ activation aggravates murine immune-mediated hepatitis

Rike Schulte, Dirk Wohlleber, Ludmilla Unrau, Bernd Geers, Christina Metzger, Annette Erhardt, Gisa Tiegs, Nico van Rooijen, Lukas C. Heukamp, Luisa Klotz, Percy A. Knolle, Linda Diehl*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

Abstract

The nuclear receptor peroxisome proliferator-activated receptor gamma (PPARγ) regulates target gene expression upon ligand binding. Apart from its effects on metabolism, PPARγ activity can inhibit the production of pro-inflammatory cytokines by several immune cells, including dendritic cells and macrophages. In chronic inflammatory disease models, PPARγ activation delays the onset and ameliorates disease severity. Here, we investigated the effect of PPARγ activation by the agonist Pioglitazone on the function of hepatic immune cells and its effect in a murine model of immune-mediated hepatitis. Cytokine production by both liver sinusoidal endothelial cells (IL-6) and in T cells ex vivo (IFNγ) was decreased in cells from Pioglitazone-treated mice. However, PPARγ activation did not decrease pro-inflammatory tumor necrosis factor alpha TNFα production by Kupffer cells after Toll-like receptor (TLR) stimulation ex vivo. Most interestingly, although PPARγ activation was shown to ameliorate chronic inflammatory diseases, it did not improve hepatic injury in a model of immune-mediated hepatitis. In contrast, Pioglitazone-induced PPARγ activation exacerbated D-galactosamine (GalN)/lipopolysaccharide (LPS) hepatitis associated with an increased production of TNFα by Kupffer cells and increased sensitivity of hepatocytes towards TNFα after in vivo Pioglitazone administration. These results unravel liver-specific effects of Pioglitazone that fail to attenuate liver inflammation but rather exacerbate liver injury in an experimental hepatitis model.

Original languageEnglish
Article number2523
JournalInternational Journal of Molecular Sciences
Volume21
Issue number7
DOIs
Publication statusPublished - 1 Apr 2020

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