title: Phospholipase C epsilon links G protein-coupled receptor activation to inflammatory astrocytic responses.
abstract: Neuroinflammation plays a major role in the pathophysiology of diseases of the central nervous system, and the role of astroglial cells in this process is increasingly recognized. Thrombin and the lysophospholipids lysophosphatidic acid and sphingosine 1-phosphate (S1P) are generated during injury and can activate G protein-coupled receptors (GPCRs) on astrocytes. We postulated that GPCRs that couple to Ras homolog gene family, member A (RhoA) induce inflammatory gene expression in astrocytes through the small GTPase responsive phospholipase Cε (PLCε). Using primary astrocytes from wild-type and PLCε knockout mice, we demonstrate that 1-h treatment with thrombin or S1P increases cyclooxygenase 2 (COX-2) mRNA levels ∼10-fold and that this requires PLCε. Interleukin-6 and interleukin-1β mRNA levels are also increased in a PLCε-dependent manner. Thrombin, lysophosphatidic acid, and S1P increase COX-2 protein expression through a mechanism involving RhoA, catalytically active PLCε, sustained activation of protein kinase D (PKD), and nuclear translocation of NF-κB. Endogenous ligands that are released from astrocytes in an in vitro wounding assay also induce COX-2 expression through a PLCε- and NF-κB-dependent pathway. Additionally, in vivo stab wound injury activates PKD and induces COX-2 and other inflammatory genes in WT but not in PLCε knockout mouse brain. Thus, PLCε links GPCRs to sustained PKD activation, providing a means for GPCR ligands that couple to RhoA to induce NF-κB signaling and promote neuroinflammation.
authors: Department of Pharmacology, School of Medicine, University of California at San Diego, La Jolla, CA 92093, USA.
authors: Stephanie S
authors: SS
authors: Dusaban
authors: Nicole H
authors: NH
authors: Purcell
authors: Edward
authors: E
authors: Rockenstein
authors: Eliezer
authors: E
authors: Masliah
authors: Min Kyung
authors: MK
authors: Cho
authors: Alan V
authors: AV
authors: Smrcka
authors: Joan Heller
authors: JH
authors: Brown
mesh_terms: D000818:Animals; D001253:Astrocytes / Q000187:drug effects / Q000201:enzymology* / Q000473:pathology*; D051546:Cyclooxygenase 2 / Q000378:metabolism; D004789:Enzyme Activation / Q000187:drug effects; D007249:Inflammation / Q000201:enzymology* / Q000473:pathology*; D008246:Lysophospholipids / Q000494:pharmacology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008954:Models, Biological; D016328:NF-kappa B / Q000378:metabolism; D054801:Phosphoinositide Phospholipase C / Q000378:metabolism*; D011493:Protein Kinase C / Q000378:metabolism; D043562:Receptors, G-Protein-Coupled / Q000378:metabolism*; D013110:Sphingosine / Q000031:analogs & derivatives / Q000494:pharmacology; D013917:Thrombin / Q000494:pharmacology; D014945:Wound Healing / Q000187:drug effects
chemical_list: D008246:Lysophospholipids; D016328:NF-kappa B; D043562:Receptors, G-Protein-Coupled; C060506:sphingosine 1-phosphate; C077623:Ptgs2 protein, mouse; D051546:Cyclooxygenase 2; C089212:protein kinase D; D011493:Protein Kinase C; D054801:Phosphoinositide Phospholipase C; C423320:phospholipase C epsilon; D013917:Thrombin; D013110:Sphingosine; C032881:lysophosphatidic acid
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