Triptolide inhibits COX‐2 expression and PGE2 release by suppressing the activity of NF‐κB and JNK in LPS‐treated microglia

Abstract

Activated microglia participate in neuroinflammation which contributes to neuronal damage in neurodegenerative diseases. Inhibition of microglial activation may have potential anti-inflammatory effects. Our laboratory has previously reported that triptolide, a natural biologically active compound extracted from Tripterygium wilfordii, could protect dopaminergic neurons from inflammation-mediated damage. However, the mechanism by which triptolide inhibits inflammation remains unknown. We reported here that inhibition of prostaglandin E(2) (PGE(2)) production could be a potential mechanism of triptolide to suppress inflammation. Triptolide suppressed c-jun NH2-terminal kinase (JNK) phosphorylation, cyclooxygenase 2 (COX-2) expression and PGE(2) production in microglial cultures treated with lipopolysaccharide (LPS). Triptolide also greatly inhibited the transcriptional activity, but not the DNA-binding activity of nuclear factor-kappaB (NF-kappaB) in microglia following LPS stimulation. These results indicate that triptolide might suppress NF-kappaB activity to down-regulate COX-2 expression. The LPS-stimulated transcriptional activity of NF-kappaB was suppressed by inhibition of p38MAPK, but not by that of JNK and extracellular signal-regulated kinase. Furthermore, the LPS-induced PGE(2) production was reduced by inhibiting these kinases. Taken together, these results suggest that triptolide may suppress neuroinflammation via a mechanism that involves inactivation of two parallel signaling pathways: p38-NF-kappaB-COX-2-PGE(2) and JNK-PGE(2).