Regulation of peroxisome proliferator-activated receptors (PPAR) α and γ- of rat brain astrocytes in the course of activation by toll-like receptor agonists

Peroxisome proliferator-activated receptors (PPAR)- and - in astrocytes play important roles in inflammatory brain pathologies. Understanding the regulation of both activity and expression levels of PPARs is an important neuroscience issue. Toll-like receptor (TLR) agonists are inflammatory stimuli that could modulate PPAR, but the mechanisms of their control in astrocytes are poorly understood. In the present study, we report that lipopolysaccharide, peptidoglycan, and flagellin, which are agonists of TLR4, TLR1/2, and TLR5, respectively, exert time- and nuclear factor kappa-light-chain-enhancer of activated B cells-dependent suppression of mRNA, protein and activity of PPAR and PPAR. In naive astrocytes, PPAR and PPAR mRNA have short turnover time (half-life about 30min for PPAR, 75min for PPAR) with a nearly two-fold stabilization after TLR-activation. p38 inhibition abolished TLR-induced stabilization. The levels of PPAR and PPAR mRNA, and protein and DNA-binding activity could be modified using c-Jun N-terminal Kinase and p38 inhibitors. In addition, the expression levels of both PPAR and PPAR isotypes were induced after inhibition of protein synthesis. This induction signifies participation of additional regulatory proteins with short life-time. They are p38-sensitive for PPAR and c-Jun N-terminal Kinase-sensitive for PPAR. Thus, PPAR and PPAR are regulated in astrocytes on mRNA and protein levels, mRNA stability, and DNA-binding activity during TLR-mediated responses. Astrocytes have the triad of PPAR, PPAR/, and PPAR in regulation of proinflammatory responses. Activation of Toll-like receptors (TLR) leads to PPAR/ overexpression, PPAR and PPAR suppression via TLR/NF-B pathway on mRNA, protein and activity levels. Mitogen-activated protein kinases (MAPK) p38 and JNK are involved in regulation of PPAR expression. p38 MAPK plays a special role in stabilization of PPAR mRNA.