Concomitant activation of extracellular signal-regulated kinase and induction of COX-2 stimulates maximum prostaglandin E2 synthesis in human airway epithelial cells.
The intracellular regulation and kinetics of prostaglandin (PG)E(2) synthesis in human airway epithelial (NCI-H292) cells was investigated. Interleukin (IL)-1beta, tumor necrosis factor (TNF)-alpha and lipopolysaccharide (LPS) all induced PGE(2) synthesis (p<0.001) and transient (5-15 min) phosphorylation of extracellular signal-regulated kinase (ERK). Phorbol myristate acetate (PMA) and calcium ionophore, A23187 further enhanced PGE(2) synthesis (p<0.001) and caused phosphorylation of ERK that was sustained for up to 16 h. COX-2 protein expression and PGE(2) synthesis were increased following exposure to combinations of stimuli that increased intracellular Ca(2+), and activated protein kinase C as well as ERK. Inhibition of ERK almost completely abrogated PGE(2) synthesis in response to all stimuli. Sustained, maximum PGE(2) synthesis was observed when cells were stimulated such that ERK phosphorylation was concomitant with increased COX-2 protein expression. These results argue against redundancy in pathways for PGE(2) synthesis, and suggest that at various stages of inflammation different stimuli may influence ERK activation and COX-2 expression, so as to tightly regulate the kinetics and amount of PGE(2) produced by airway epithelial cells in response to lung inflammation.
Petrovic
Nenad
N
Lung Institute of Western Australia and Centre for Asthma, Allergy and Respiratory Research, The University of Western Australia, Perth, Australia.
Knight
Darryl A
DA
Bomalaski
John S
JS
Thompson
Philip J
PJ
Misso
Neil L A
NL
D000001:Calcimycin / Q000494:pharmacology; D002118:Calcium / Q000378:metabolism; D051546:Cyclooxygenase 2 / Q000096:biosynthesis*; D015232:Dinoprostone / Q000096:biosynthesis*; D004790:Enzyme Induction; D004847:Epithelial Cells / Q000187:drug effects / Q000378:metabolism; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism*; D006801:Humans; D053583:Interleukin-1beta / Q000494:pharmacology; D007476:Ionophores / Q000494:pharmacology; D007700:Kinetics; D008070:Lipopolysaccharides / Q000494:pharmacology; D010741:Phospholipases A / Q000378:metabolism; D010766:Phosphorylation; D011014:Pneumonia / Q000473:pathology; D011493:Protein Kinase C / Q000378:metabolism; D012137:Respiratory System / Q000166:cytology*; D015398:Signal Transduction; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology
D053583:Interleukin-1beta; D007476:Ionophores; D008070:Lipopolysaccharides; D014409:Tumor Necrosis Factor-alpha; D000001:Calcimycin; D051546:Cyclooxygenase 2; D011493:Protein Kinase C; D048049:Extracellular Signal-Regulated MAP Kinases; D010741:Phospholipases A; D015232:Dinoprostone; D013755:Tetradecanoylphorbol Acetate; D002118:Calcium