Induction of COX-2 in human airway cells by manganese: role of PI3K/PKB, p38 MAPK, PKCs, Src, and glutathione depletion.
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 pathogenesis of lung inflammation. In this study, the effect of manganese-chloride (manganese) on COX-2 expression 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, manganese treatment led to activation of ERKs, p38 MAPK, JNKs, ATF-2, and PKB, but not NF-kappaB, and also cellular 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 (laryngeal). 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.
Jang
Byeong-Churl
BC
Department of Medical Genetic Engineering, School of Medicine, Keimyung University, 194 Dongsan-dong, Jung-gu, Daegu 700-712, South Korea. jangbc12@kmu.ac.kr
D002478:Cells, Cultured; D002712:Chlorides / Q000633:toxicity*; D051546:Cyclooxygenase 2 / Q000096:biosynthesis* / Q000235:genetics; D004305:Dose-Response Relationship, Drug; D004785:Environmental Pollutants / Q000633:toxicity*; D004790:Enzyme Induction / Q000187:drug effects; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects; D005978:Glutathione / Q000378:metabolism*; D006801:Humans; D017895:Manganese Compounds; D019869:Phosphatidylinositol 3-Kinases / Q000096:biosynthesis; D010770:Phosphotransferases / Q000096:biosynthesis*; D011493:Protein Kinase C / Q000096:biosynthesis; D051057:Proto-Oncogene Proteins c-akt / Q000096:biosynthesis; D012313:RNA / Q000378:metabolism; D020545:Respiratory Mucosa / Q000187:drug effects* / Q000201:enzymology; D014158:Transcription, Genetic / Q000187:drug effects / Q000235:genetics; D015854:Up-Regulation / Q000187:drug effects / Q000235:genetics; D048051:p38 Mitogen-Activated Protein Kinases / Q000096:biosynthesis; D019061:src-Family Kinases / Q000096:biosynthesis
D002712:Chlorides; D004785:Environmental Pollutants; D017895:Manganese Compounds; D012313:RNA; D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human; D010770:Phosphotransferases; D019869:Phosphatidylinositol 3-Kinases; D019061:src-Family Kinases; D051057:Proto-Oncogene Proteins c-akt; D011493:Protein Kinase C; D048051:p38 Mitogen-Activated Protein Kinases; D005978:Glutathione; C025340:manganese chloride