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

Fernand Gobeil, Sylvie G. Bernier, Alejandro Vazquez-Tello, Sonia Brault, Martin H. Beauchamp, Christiane Quiniou, Anne Marilise Marrache, Daniella Checchin, Florian Sennlaub, Xin Hou, Mony Nader, Ghassan Bkaily, Alfredo Ribeiro-da-Silva, Edward J. Goetzl, Sylvain Chemtob

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124 Scopus citations

Abstract

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 (LPA1R) was revealed in unstimulated porcine cerebral microvascular endothelial cells (pCM-VECs), LPA1R 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 LPA1Rs are dually sequestrated in caveolin-1 and clathrin subcompartments, 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 nitricoxide 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.

Original languageBritish English
Pages (from-to)38875-38883
Number of pages9
JournalJournal of Biological Chemistry
Volume278
Issue number40
DOIs
StatePublished - 3 Oct 2003

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