Role of p53 methylation in manganese-induced cyclooxygenase-2 expression in BV2 microglial cells

Abstract

Manganese (Mn) is an essential cofactor for many enzymes and plays an important role in normal growth and development. However, excess exposure to manganese (Mn) may be an important environmental factor leading to neurodegeneration. The overexpression of microglial cyclooxygenase-2 (COX-2) plays a key role in neuroinflammation in neurodegenerative diseases. The existing data suggest that Mn can induce neuroinflammation by up-regulating COX-2 expression. However, the mechanisms involved in Mn-induced microglial COX-2 up-regulation remain to be determined. The aim of this study was to investigate the role of p53 in Mn-induced COX-2 expression in microglial cells. The results showed that Mn exposure induced the up-regulation of COX-2 and inhibited the expression of p53 in BV2 microglial cells. The addition of p53 activator and the over-expression of p53 blocked the expression of COX-2 and prostaglandin E2 (PGE2), a COX-2 downstream effector, induced by Mn. Further, Mn increased the methylation of p53 DNA in microglia, while the addition of demethylation reagent 5-Aza-dC enhanced the expression of p53 but decreased the expression of COX-2. These results suggested that Mn may inhibit p53 expression through induction of DNA methylation, which can further induce the expression of COX-2 in microglial cells.