Kumagai Takeshi, Nakamura Yoshimasa, Osawa Toshihiko, Uchida Koji
Laboratory of Food and Biodynamics, Graduate School of Bioagricultural Sciences, Nagoya University, Nagoya 464-8601, Japan.
Arch Biochem Biophys. 2002 Jan 15;397(2):240-5. doi: 10.1006/abbi.2001.2601.
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.
COX-2可被多种刺激迅速表达，并在游离花生四烯酸转化为前列腺素（PGs）的过程中起关键作用。4-羟基-2-壬烯醛（HNE）是脂质过氧化终产物之一，最近被确定为大鼠上皮细胞RL34细胞中一种有效的COX-2诱导剂（熊谷等人，《生物化学与生物物理学研究通讯》，2000年，第273卷，第437 - 441页）。在此，我们主要聚焦于p38丝裂原活化蛋白激酶（MAPK）途径的激活，研究了HNE诱导COX-2的分子机制。（i）HNE在5分钟内诱导p38 MAPK和MKK3/MKK6磷酸化，以及（ii）p38 MAPK特异性抑制剂SB203580抑制HNE诱导的COX-2表达，这些观察结果表明p38 MAPK途径参与了HNE诱导的COX-2表达。p38 MAPK的过表达增强了HNE诱导的COX-2表达，而显性负性p38 MAPK的过表达则抑制了该表达。此外，我们还发现HNE通过p38 MAPK途径使COX-2 mRNA稳定，从而上调COX-2表达。
