Regulation of peroxisome proliferator-activated receptor β/δ expression and activity levels by toll-like receptor agonists and MAP kinase inhibitors in rat astrocytes

Peroxisome proliferator-activated receptor beta/delta (PPAR beta/delta) is a potential regulator of neuroinflammation. Toll-like receptors (TLR) are innate immunity-related receptors of inflammatory stimuli. In the present report, we evaluate the molecular mechanisms of regulation of mRNA, protein, and transcriptional activity levels of PPAR beta/delta by agonists of TLR4, TLR1/2, and TLR5, using lipopolysaccharide (LPS), peptidoglycan, and flagellin, respectively. We found that these stimuli increase the PPAR beta/delta levels in astrocytes. Expression and activity of PPAR beta/delta are separately regulated by inhibitors of p38, MEK1/2, extracellular signal-regulated kinases 1/2, and c-Jun N-terminal Kinase mitogen-activated protein kinases. The LPS-induced kinetics of PPAR beta/delta expression is similar to that of the proinflammatory gene cyclooxygenase 2. Moreover, for both genes the expression depends on nuclear factor kappa-light-chain-enhancer of activated B cells and p38, and is induced after inhibition of protein synthesis. The up-regulation of the expression after inhibition of protein synthesis signifies the participation of a labile protein in regulation of PPAR beta/delta expression. In contrast to cyclooxygenase 2, the cycloheximide-sensitive PPAR beta/delta expression was not responsive to nuclear factor kappa-light-chain-enhancer of activated B cells inhibition. Measurements of PPAR beta/delta mRNA stability showed that the PPAR beta/delta mRNA levels are regulated post-transcriptionally. We found that in LPS-stimulated astrocytes, the half-life of PPAR beta/delta mRNA was 50 min. Thus, we demonstrate that PPAR beta/delta expression and activity are regulated in TLR agonist-stimulated astrocytes by mechanisms that are widely used for regulation of proinflammatory genes.