Identification of a serum component that regulates cyclooxygenase-2 gene expression in cooperation with 4-hydroxy-2-nonenal.
Atherosclerosis is a disorder of lipid metabolism as well as a chronic inflammatory disease. Cyclooxygenase-2 (COX-2), an inducible isoform responsible for high levels of prostaglandin production during inflammation and immune responses, mediates a variety of biological actions involved in vascular pathophysiology. We have previously shown that COX-2 gene expression is dramatically induced by a lipid-derived endogenous electrophile, 4-hydroxy-2-nonenal (HNE) (Kumagai, T., Matsukawa, N., Kaneko, Y., Kusumi, Y., Mitsumata, M., and Uchida, K. (2004) J. Biol. Chem. 279, 48389-48396). In the present study, based on the finding that HNE induced COX-2 expression only in the serum-containing media, we characterized a serum component essential for the HNE-induced COX-2 induction and found that low density lipoprotein (LDL) that had been denatured by freeze-thawing or oxidized LDL might be involved in the COX-2 induction. Moreover, we characterized the cellular events triggered by the combined stimulus of HNE and oxidized LDL and established that COX-2 induction is regulated by two sets of signaling mechanisms, one for the up-regulation of the scavenger receptor CD36 by HNE and one for the CD36-mediated COX induction by oxidized LDL. These findings represent a demonstration of a link between lipoprotein modification and activation of the inflammatory potential of macrophages.
Kanayama
Masaya
M
Graduate School of Bioagricultural Sciences, Nagoya University, Nagoya 464-8601, Japan.
Yamaguchi
Satoru
S
Shibata
Takahiro
T
Shibata
Noriyuki
N
Kobayashi
Makio
M
Nagai
Ryoji
R
Arai
Hiroyuki
H
Takahashi
Kazuhiko
K
Uchida
Koji
K
D000447:Aldehydes / Q000494:pharmacology*; D018955:CD36 Antigens / Q000235:genetics*; D051546:Cyclooxygenase 2 / Q000235:genetics*; D015853:Cysteine Proteinase Inhibitors; D005786:Gene Expression Regulation; D006801:Humans; D008077:Lipoproteins, LDL / Q000502:physiology*; D015398:Signal Transduction
D000447:Aldehydes; D018955:CD36 Antigens; D015853:Cysteine Proteinase Inhibitors; D008077:Lipoproteins, LDL; C099252:oxidized low density lipoprotein; D051546:Cyclooxygenase 2; C027576:4-hydroxy-2-nonenal