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

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.

Secretome analysis of human schwann cells derived from malignant peripheral nerve sheath tumor

“…Forty five proteins of our list were found to be involved in PI3K‐Akt signalling pathway which has also been described in the control of myelination [20]. Persistent signalling via the PI3K/AKT/mTOR pathway is a major driver of NF1‐associated MPNST malignancy [21, 22]. Multiple lines of evidence strongly support a role for deregulated PI3K/AKT/mTOR signalling in MPNST [23].…”

Age and sex differences on anti-hyperglycemic medication exposure and risk of newly diagnosed multiple sclerosis in propensity score matched type 2 diabetics

“…In addition, injectable insulin is used in late-stage T2D patients who are not responding to other pharmacotherapies to directly activate the insulin receptor. These therapeutics target the immune system and each have distinct immunomodulatory profiles which may impact the pathogenesis of MS [ 13 , 14 , 15 , 16 ].…”