Ceramide induction of COX-2 and PGE(2) in pulmonary A549 cells does not involve activation of NF-kappaB.
Ceramide is generated by the hydrolysis of membrane sphingomyelin by sphingomyelinase (SMase) and is implicated in multiple signaling pathways, including activation of NF-kappaB. As NF-kappaB is pivotal in the expression of numerous genes associated with airway inflammation and asthma, the effects of ceramide and SMase were examined in human pulmonary A549 cells. Ceramide and SMase both induced cyclooxygenase (COX)-2 protein expression and stimulated PGE(2) release. However, neither ceramide nor SMase induced NF-kappaB DNA-binding, loss of IkappaBalpha, or NF-kappaB-dependent transcription. Both ceramide and SMase were efficient inducers of the extracellular regulated kinase (ERK), but not Jun N-terminal kinase (JNK) or p38 mitogen-activated protein kinase. Since ERK is implicated in arachidonic acid availability, these data partly explain the ability of ceramide to induce PGE(2) release. However, as ERK is not required for IL-1beta-dependent induction of COX-2, the mechanism of ceramide and SMase induction of COX-2 remains unclear.
Newton
R
R
Department of Thoracic Medicine, Imperial College of Science, Technology and Medicine, National Heart and Lung Institute, Dovehouse Street, London, SW3 6LY, United Kingdom.
Hart
L
L
Chung
K F
KF
Barnes
P J
PJ
D001952:Bridged-Ring Compounds / Q000494:pharmacology; D002518:Ceramides / Q000378:metabolism / Q000502:physiology*; D051546:Cyclooxygenase 2; D015232:Dinoprostone / Q000378:metabolism*; D004789:Enzyme Activation; D004790:Enzyme Induction; D006801:Humans; D007527:Isoenzymes / Q000096:biosynthesis* / Q000235:genetics; D008168:Lung / Q000473:pathology; D008565:Membrane Proteins; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism*; D009636:Norbornanes; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology; D011451:Prostaglandin-Endoperoxide Synthases / Q000096:biosynthesis* / Q000235:genetics; D013108:Sphingomyelin Phosphodiesterase / Q000502:physiology; D013109:Sphingomyelins / Q000378:metabolism; D013859:Thiocarbamates; D013871:Thiones / Q000494:pharmacology; D014158:Transcription, Genetic / Q000187:drug effects; D014407:Tumor Cells, Cultured
D001952:Bridged-Ring Compounds; D002518:Ceramides; D007527:Isoenzymes; D008565:Membrane Proteins; D016328:NF-kappa B; D009636:Norbornanes; D010726:Phosphodiesterase Inhibitors; D013109:Sphingomyelins; D013859:Thiocarbamates; D013871:Thiones; C046498:tricyclodecane-9-yl-xanthogenate; D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human; D011451:Prostaglandin-Endoperoxide Synthases; D020928:Mitogen-Activated Protein Kinases; D013108:Sphingomyelin Phosphodiesterase; D015232:Dinoprostone