Effect of Peroxisome Proliferator-Activated Receptor Alpha Activators on Tumor Necrosis Factor Expression in Mice during Endotoxemia

Abstract

Inflammatory mediators orchestrate the host immune and metabolic response to acute bacterial infections and mediate the events leading to septic shock. Tumor necrosis factor (TNF) has long been identified as one of the proximal mediators of endotoxin action. Recent studies have implicated peroxisome proliferator-activated receptor alpha (PPARα) as a potential target to modulate regulation of the immune response. Since PPARα activators, which are hypolipidemic drugs, are being prescribed for a significant population of older patients, it is important to determine the impact of these drugs on the host response to acute inflammation. Therefore, we examined the role of PPARα activators on the regulation of TNF expression in a mouse model of endotoxemia. CD-1 mice treated with dietary fenofibrate or Wy-14,643 had fivefold-higher lipopolysaccharide (LPS)-induced TNF plasma levels than LPS-treated control-fed animals. Higher LPS-induced TNF levels in drug-fed animals were reflected physiologically in significantly lower glucose levels in plasma and a significantly lower 50% lethal dose than those in LPS-treated control-fed animals. Utilizing PPARα wild-type (WT) and knockout (KO) mice, we showed that the effect of fenofibrate on LPS-induced TNF expression was indeed mediated by PPARα. PPARα WT mice fed fenofibrate also had a fivefold increase in LPS-induced TNF levels in plasma compared to control-fed animals. However, LPS-induced TNF levels were significantly decreased and glucose levels in plasma were significantly increased in PPARα KO mice fed fenofibrate compared to those in control-fed animals. Data from peritoneal macrophage studies indicate that Wy-14,643 modestly decreased TNF expression in vitro. Similarly, overexpression of PPARα in 293T cells decreased activity of a human TNF promoter-luciferase construct. The results from these studies suggest that any anti-inflammatory activity of PPARα in vivo can be masked by other systemic effects of PPARα activators.

PPAR‐α and ‐γ but not ‐δ agonists inhibit airway inflammation in a murine model of asthma: in vitro evidence for an NF‐κB‐independent effect

“…In contrast, in mice injected with lipopolysaccharide (LPS), activation of PPAR‐ α induced a significant increase in plasma tumour necrosis factor‐ α (TNF‐ α ) levels. This result was confirmed to be mediated by PPAR‐ α using deficient mice (Hill et al ., 1999). Contradictory data have also been generated concerning the role of PPAR‐ γ in inflammatory models in vivo .…”

Inhibition of glial cell proinflammatory activities by peroxisome proliferator‐activated receptor gamma agonist confers partial protection during antimyelin oligodendrocyte glycoprotein demyelination in vitro

“…However, PPAR‐γ mRNA was specifically up‐regulated only when anti‐MOG demyelination was induced. Moreover, a delayed expression of PPAR‐γ was confirmed (Hill et al, 1999), in that a 48 hr incubation was required for its expression in the demyelinating cultures. As shown previously in the aggregate culture system (Pouly et al, 1997), anti‐MOG‐mediated demyelination strongly activated microglia, suggesting that these cells are responsible for the expression of PPAR‐γ.…”

The PPARα agonist fenofibrate attenuates disruption of dopamine function in a maternal immune activation rat model of schizophrenia

“…13,47,51,52 The mechanisms of anti-inflammatory and neuroprotective actions by PPARα in the CNS have not been fully clarified. One hypothesis is that PPARα activation negatively regulates the signaling of nuclear factor kappa-light-chain-enhancer of activated B cells (NFκB) and the activator protein 1 (AP-1), 54 the expression of tumor necrosis factor-α (TNF-α) 55 as well as the production of cytokines and interferons. 56 The activation of PPARα has been reported to increase the brain synthesis of oleoylethanolamide (OEA) and palmitoylethanolamide (PEA).…”