The inhibitory effect of raloxifene on lipopolysaccharide-induced nitric oxide production in RAW264.7 cells is mediated through a ROS/p38 MAPK/CREB pathway to the up-regulation of heme oxygenase-1 independent of estrogen receptor

Title
The inhibitory effect of raloxifene on lipopolysaccharide-induced nitric oxide production in RAW264.7 cells is mediated through a ROS/p38 MAPK/CREB pathway to the up-regulation of heme oxygenase-1 independent of estrogen receptor
Author(s)
이신애[이신애]김은예[김은예]전우광[전우광]우창훈최종선[최종선]한상화[한상화]김병철[김병철]
Keywords
15-DEOXY-DELTA(12,14)-PROSTAGLANDIN J(2); MURINE MACROPHAGES; OXIDATIVE STRESS; CARBON-MONOXIDE; EXPRESSION; INFLAMMATION; TAMOXIFEN; GENE
Issue Date
201102
Publisher
ELSEVIER FRANCE-EDITIONS SCIENTIFIQUES MEDICALES ELSEVIER
Citation
BIOCHIMIE, v.93, no.2, pp.168 - 174
Abstract
In this study, we demonstrate that raloxifene, a selective estrogen receptor modulator, is a potent inducer of the anti-inflammatory enzyme heme oxygenase-1 (HO-1). In RAW264.7 macrophages, raloxifene induced HO-1 mRNA and protein expression. Pretreatment of 10182780, an estrogen receptor (ER) antagonist or knock-down of endogenous ER alpha or ER beta gene by RNA interference failed to reverse raloxifene-mediated HO-1 induction, indicating an estrogen receptor-independent mechanism. Interestingly, the raloxifene-induced HO-1 expression was suppressed by reactive oxygen species (ROS) scavengers, including glutathione, TEMPO, Me(2)SO, 1,10-phenanthroline, or allopurinol. In addition, buthionine sulfoximine, an inhibitor of reduced glutathione synthesis, or Fe2+/Cu2+ ions enhanced the positive effect of raloxifene on HO-1 expression. Consistent with these findings, raloxifene induced production of intracellular ROS and increased xanthine oxidase activity in vitro. Additional experiments revealed the involvement of mitogen-activated protein kinase (MAPK) kinase6 and p38 MAPK in the up-regulation of HO-1 by raloxifene and identified p38 MAPK as a downstream effector of ROS. Furthermore, the ROS-p38 MAPK cascade targeted the transcription factor cAMP-responsive element-binding protein (CREB). Finally, the functional significance of HO-1 induction was revealed by raloxifene-mediated inhibition of inducible nitric oxide synthase expression and nitric oxide production, a response reversed by the inhibition of HO-1 protein synthesis or blockade of p38 MAPK or xanthine oxidase activity. Therefore, identification of ROS-p38 MAPK-CREB-linked cascade as cellular relays in raloxifene-mediated HO-1 expression defines the signaling events that could participate in raloxifene-mediated anti-inflammatory response. (C) 2010 Elsevier Masson SAS. All rights reserved.
URI
http://hdl.handle.net/YU.REPOSITORY/25685http://dx.doi.org/10.1016/j.biochi.2010.09.007
ISSN
0300-9084
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의과대학 > 약리학교실 > Articles
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