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

Abstract Peroxisome proliferator‐activated receptor β/δ (PPARβ/δ) 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 PPARβ/δ by agonists of TLR4, TLR1/2, and TLR5, using lipopolysaccharide (LPS), peptidoglycan, and flagellin, respectively. We found that these stimuli increase the PPARβ/δ levels in astrocytes. Expression and activity of PPARβ/δ 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 PPARβ/δ 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 PPARβ/δ expression. In contrast to cyclooxygenase 2, the cycloheximide‐sensitive PPARβ/δ expression was not responsive to nuclear factor kappa‐light‐chain‐enhancer of activated B cells inhibition. Measurements of PPARβ/δ mRNA stability showed that the PPARβ/δ mRNA levels are regulated post‐transcriptionally. We found that in LPS‐stimulated astrocytes, the half‐life of PPARβ/δ mRNA was 50 min. Thus, we demonstrate that PPARβ/δ expression and activity are regulated in TLR agonist‐stimulated astrocytes by mechanisms that are widely used for regulation of proinflammatory genes. image Protein expression level of nuclear receptor PPARβ/δ is important for functions of this transcription factor. We investigate the regulatory mechanisms of PPARβ/δ in rat primary astrocytes stimulated by agonists of toll‐like receptors (TLR): TLR4, TLR1/2, and TLR5. Expression, activity, mRNA stability, and superinduction of PPARβ/δ were up‐regulated after TLR stimulation. These processes are sensitive to MAPKs and NF‐kB inhibitors. Superinduction is up‐regulation of mRNA expression after inhibition of protein synthesis.