Pioglitazone-Mediated Peroxisome Proliferator-Activated Receptor γ Activation Aggravates Murine Immune-Mediated Hepatitis.

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

doi:10.3390/ijms21072523

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.

Highlights

The transcription factor nuclear receptor peroxisome proliferator-activated receptor gamma (PPARγ) has been shown to mediate anti-inflammatory effects on several immune cell types [1,2]
Mice were fed with the PPARγ ligand Pioglitazone (Pio) or the vehicle carboxy-methyl-cellulose alone for 7 days, after which liver sinusoidal endothelial cells (LSEC) or Kupffer cells were isolated from the liver, or T lymphocytes from the spleen
PPARγ activation in vivo inhibited the function of splenic T cells as their ability to produce IFNγ (Figure 1B) ex vivo upon anti-CD3ε/CD28 stimulation was severely reduced over time (Figure 1B)

Summary

Introduction

The transcription factor nuclear receptor peroxisome proliferator-activated receptor gamma (PPARγ) has been shown to mediate anti-inflammatory effects on several immune cell types [1,2]. PPARγ negatively affects pro-inflammatory cell signaling, either via competition for co-activators or via transrepression through physical interaction with pro-inflammatory transcription factors, in particular NF-κB [2,3]. PPARγ agonists can be activated by endogenous ligands, such as polyunsaturated fatty acids and prostanoids like the prostaglandin D2 (PG-D2) metabolite 15-deoxy-D PG-J2 [4]. Various cell types of the immune system are affected in their function after PPARγ activation. In peripheral blood monocytes and peritoneal macrophages, PPARγ can downregulate the production of pro-inflammatory cytokines, like interleukin (IL) 1β, IL-6 and TNFα, and affects the uptake and destruction of pathogens [8]. We could show that PPARγ activation interferes with retinoic acid receptor-related orphan receptor (ROR)γt transcription and Th17 differentiation [9]

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Results

Conclusion