Modulation of pro-inflammatory gene expression by nuclear lysophosphatidic acid receptor type-1

被引:115
作者
Gobeil, F
Bernier, SG
Vazquez-Tello, A
Brault, S
Beauchamp, MH
Quiniou, C
Marrache, AM
Checchin, D
Sennlaub, F
Hou, X
Nader, M
Bkaily, G
Ribeiro-da-Silva, A
Goetzl, EJ
Chemtob, S
机构
[1] Univ Sherbrooke, Dept Anat & Cell Biol, Sherbrooke, PQ J1H 5N4, Canada
[2] Hop St Justine, Ctr Rech, Dept Pediat, Montreal, PQ H3T 1C5, Canada
[3] Hop St Justine, Ctr Rech, Dept Ophthalmol, Montreal, PQ H3T 1C5, Canada
[4] Hop St Justine, Ctr Rech, Dept Pharmacol, Montreal, PQ H3T 1C5, Canada
[5] McGill Univ, Dept Pharmacol & Therapeut, Montreal, PQ H3G 1Y6, Canada
[6] Univ Calif San Francisco, Dept Med Microbiol Immunol, San Francisco, CA 94143 USA
关键词
D O I
10.1074/jbc.M212481200
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
Lysophosphatidic acid (LPA) is a bioactive molecule involved in inflammation, immunity, wound healing, and neoplasia. Its pleiotropic actions arise presumably by interaction with their cell surface G protein-coupled receptors. Herein, the presence of the specific nuclear lysophosphatidic acid receptor-1 (LPA(1)R) was revealed in unstimulated porcine cerebral microvascular endothelial cells (pCMVECs), LPA(1)R stably transfected HTC4 rat hepatoma cells, and rat liver tissue using complementary approaches, including radioligand binding experiments, electron- and cryomicroscopy, cell fractionation, and immunoblotting with three distinct antibodies. Co-immunoprecipitation studies in enriched plasmalemmal fractions of unstimulated pCMVEC showed that LPA(1)Rs are dually sequestrated in caveolin-1 and clathrin sub-compartments, whereas in nuclear fractions LPA1R appeared primarily in caveolae. Immunofluorescent assays using a cell-free isolated nuclear system confirmed LPA1R and caveolin-1 co-localization. In pCMVEC, LPA-stimulated increases in cyclooxygenase-2 and inducible nitric-oxide synthase RNA and protein expression were insensitive to caveolea-disrupting agents but sensitive to LPA-generating phospholipase A(2) enzyme and tyrosine kinase inhibitors. Moreover, LPA-induced increases in Ca2+ transients and/or iNOS expression in highly purified rat liver nuclei were prevented by pertussis toxin, phosphoinositide 3-kinase/Akt inhibitor wortmannin and Ca2+ chelator and channel blockers EGTA and SK&F96365, respectively. This study describes for the first time the nucleus as a potential organelle for LPA intracrine signaling in the regulation of pro-inflammatory gene expression.
引用
收藏
页码:38875 / 38883
页数:9
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