Signaling mechanism underlying COX-2 induction by lysophosphatidylcholine.
Lysophosphatidylcholine, a component of oxidized low density lipoprotein, is critical for pathological conditions including atherosclerosis. However, the signaling mechanism of lysophosphatidylcholine remains poorly understood. Here we reported that lysophosphatidylcholine induces phosphorylation of p38 and the transcription factors, CREB and ATF-1 with concomitant up-regulation of cyclooxygenase-2 expression in cultured vascular endothelial cells. Lysophosphatidylcholine induced p38 phosphorylation in a time- and concentration-dependent manner partly via pathway depending on protein tyrosine kinase. Both lysophosphatidylcholine-stimulated phosphorylation of CREB and ATF-1 and lysophosphatidylcholine-increased expression of cyclooxygenase-2 mRNA and protein were effectively inhibited by a combination of SB203580 and PD98059, specific inhibitors of p38 and MEK1, respectively, as well as Ro31-8220 and H89, potent inhibitors of MSK1. These results suggest that both p38 and ERK may function as upstream signaling pathways capable of activating CREB and ATF-1 with subsequent induction of cyclooxygenase-2 expression by lysophosphatidylcholine.
Rikitake
Y
Y
First Department of Internal Medicine, Kobe University School of Medicine, 7-5-1, Kusunoki-cho, Chuo-ku, Kobe, 650-0017, Japan. rikitake@med.kobe-u.ac.jp
Hirata
K
K
Kawashima
S
S
Takeuchi
S
S
Shimokawa
Y
Y
Kojima
Y
Y
Inoue
N
N
Yokoyama
M
M
D051697:Activating Transcription Factor 1; D000818:Animals; D002417:Cattle; D002478:Cells, Cultured; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism; D051546:Cyclooxygenase 2; D004268:DNA-Binding Proteins; D004730:Endothelium, Vascular / Q000187:drug effects / Q000378:metabolism*; D004790:Enzyme Induction; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005419:Flavonoids / Q000494:pharmacology; D007093:Imidazoles / Q000494:pharmacology; D007211:Indoles / Q000494:pharmacology; D007527:Isoenzymes / Q000096:biosynthesis / Q000235:genetics*; D007546:Isoquinolines / Q000494:pharmacology; D008244:Lysophosphatidylcholines / Q000494:pharmacology*; D020935:MAP Kinase Signaling System; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D010766:Phosphorylation; D011451:Prostaglandin-Endoperoxide Synthases / Q000096:biosynthesis / Q000235:genetics*; D011725:Pyridines / Q000494:pharmacology; D012333:RNA, Messenger / Q000096:biosynthesis; D013449:Sulfonamides; D014157:Transcription Factors / Q000378:metabolism; D015854:Up-Regulation; D048051:p38 Mitogen-Activated Protein Kinases
D051697:Activating Transcription Factor 1; D017362:Cyclic AMP Response Element-Binding Protein; D004268:DNA-Binding Proteins; D004791:Enzyme Inhibitors; D005419:Flavonoids; D007093:Imidazoles; D007211:Indoles; D007527:Isoenzymes; D007546:Isoquinolines; D008244:Lysophosphatidylcholines; D011725:Pyridines; D012333:RNA, Messenger; D013449:Sulfonamides; D014157:Transcription Factors; D051546:Cyclooxygenase 2; D011451:Prostaglandin-Endoperoxide Synthases; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; C063509:N-(2-(4-bromocinnamylamino)ethyl)-5-isoquinolinesulfonamide; C093642:SB 203580; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one; C064758:Ro 31-8220