Induction of COX-2 in human airway cells by manganese: Role of PI3K/PKB, p38 MAPK, PKCs, Src, and glutathione depletion

Abstract

The exposure of manganese is believed to be the risk of respiratory diseases. COX-2 is a protein involved in biosynthesis of inflammatory prostaglandins. Evidence suggests that COX-2 involves in the pathogen- esis of lung inflammation. In this study, the effect of manganese–chloride (manganese) on COX-2 expres- sion in A549 human lung epithelial cells was investigated. Treatment with manganese induced COX-2 at both protein and mRNA levels that were due to COX-2 transcriptional activation. Interestingly, manga- nese treatment led to activation of ERKs, p38 MAPK, JNKs, ATF-2, and PKB, but not NF-jB, and also cel- lular GSH depletion in A549 cells. Importantly, the manganese-induced COX-2 expression was suppressed by treatment with the inhibitor of p38 MAPK (SB203580), PI3K/PKB (LY294002), PKCs (GO6983, GF109203X, Rottlerin), Src (PP1), or the thiol-containing compound (NAC). There was crosstalk between p38 MAPK and GSH depletion or Src in response to manganese signal. Induction of COX-2 by manganese was also seen in different human airway cells, including H292 (bronchial) or Hep2 (laryn- geal). These results collectively suggest that manganese induces COX-2 by transcriptional up-regulation in human airway cells and the induction appears to be cooperatively mediated via multiple signaling pathways and GSH depletion. 2008 Elsevier Ltd. All rights reserved. Keywords: Manganese COX-2 PI3K/PKB p38 MAPK PKCs Src GSH A549 cells