Role of p38 mitogen-activated protein kinase in the 4-hydroxy-2-nonenal-induced cyclooxygenase-2 expression.
COX-2 is rapidly expressed by various stimuli and plays a key role in conversion of free arachidonic acid to prostaglandins (PGs). 4-Hydroxy-2-nonenal (HNE), one of the lipid peroxidation end-products, has been recently identified as a potent COX-2 inducer in rat epithelial cell RL34 cells (Kumagai et al. (2000) Biochem. Biophys. Res. Commun. 273, 437-441). Here we investigated the molecular mechanism underlying the COX-2 induction by HNE mainly focusing on the activation of p38 mitogen-activated protein kinase (MAPK) pathways. The observations that (i) HNE induced phosphorylation of p38 MAPK and MKK3/MKK6 within 5 min and that (ii) SB203580, a p38 MAPK-specific inhibitor, suppressed the HNE-induced COX-2 expression suggested that the p38 MAPK pathway was involved in the HNE-induced COX-2 expression. Overexpression of p38 MAPK enhanced the HNE-induced COX-2 expression, whereas the overexpression of dominant negative p38 MAPK suppressed it. Furthermore, we also found that HNE upregulated the COX-2 expression by the stabilization of COX-2 mRNA via the p38 MAPK pathway.
Kumagai
Takeshi
T
Laboratory of Food and Biodynamics, Graduate School of Bioagricultural Sciences, Nagoya University, Nagoya 464-8601, Japan.
Nakamura
Yoshimasa
Y
Osawa
Toshihiko
T
Uchida
Koji
K
D000447:Aldehydes / Q000494:pharmacology*; D000818:Animals; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000378:metabolism; D051546:Cyclooxygenase 2; D004847:Epithelial Cells / Q000378:metabolism; D007527:Isoenzymes / Q000096:biosynthesis*; D008099:Liver / Q000166:cytology / Q000378:metabolism; D048371:MAP Kinase Kinase 3; D048669:MAP Kinase Kinase 6; D020929:Mitogen-Activated Protein Kinase Kinases / Q000378:metabolism; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D008954:Models, Biological; D010766:Phosphorylation; D011451:Prostaglandin-Endoperoxide Synthases / Q000096:biosynthesis*; D011505:Protein-Tyrosine Kinases / Q000378:metabolism; D051381:Rats; D015398:Signal Transduction; D048051:p38 Mitogen-Activated Protein Kinases
D000447:Aldehydes; D007527:Isoenzymes; D051546:Cyclooxygenase 2; D011451:Prostaglandin-Endoperoxide Synthases; D011505:Protein-Tyrosine Kinases; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D048371:MAP Kinase Kinase 3; D048669:MAP Kinase Kinase 6; D020929:Mitogen-Activated Protein Kinase Kinases; C027576:4-hydroxy-2-nonenal