Cysteinyl-leukotrienes are released from astrocytes and increase astrocyte proliferation and glial fibrillary acidic protein via cys-LT1 receptors and mitogen-activated protein kinase pathway

• Published in: The European journal of neuroscience Vol. 20; no. 6; pp. 1514 - 1524
• Main Authors: Ciccarelli, Renata, D'Alimonte, Iolanda, Santavenere, Clara, D'Auro, Mariagrazia, Ballerini, Patrizia, Nargi, Eleonora, Buccella, Silvana, Nicosia Folco, Simonetta, Giancarlo, Caciagli, Francesco, Di Iorio, Patrizia
• Format: Journal Article
• Language: English
• Published: Oxford, UK Blackwell Science Ltd 01-09-2004
• Subjects: Adenosine Triphosphate - analogs & derivatives; Adenosine Triphosphate - pharmacology; Animals; Animals, Newborn; Astrocytes - metabolism; astrogliosis; Blotting, Northern - methods; Blotting, Western - methods; Calcimycin - pharmacology; Cell Division - physiology; Cell Survival; Cells, Cultured; Cerebral Cortex - cytology; Cerebral Cortex - metabolism; cys-LT1 receptors; Cysteine - classification; Cysteine - metabolism; Cysteine - pharmacology; cysteinyl-leukotriene release; Dose-Response Relationship, Drug; Drug Interactions; Enzyme Inhibitors - pharmacology; Glial Fibrillary Acidic Protein - metabolism; Glucose - deficiency; Glutathione Transferase - genetics; Glutathione Transferase - metabolism; Hypoxia; Immunoenzyme Techniques - methods; Ionophores - pharmacology; Leukotrienes - classification; Leukotrienes - metabolism; Leukotrienes - pharmacology; Lipoxygenase - genetics; Lipoxygenase - metabolism; MAPK pathway; Membrane Proteins - physiology; Mitogen-Activated Protein Kinases - physiology; rat astrocytes; Rats; Receptors, Leukotriene - physiology; Reverse Transcriptase Polymerase Chain Reaction - methods; RNA, Messenger - metabolism; Signal Transduction - drug effects; Signal Transduction - physiology; Thionucleotides - pharmacology; Thymidine - metabolism; Time Factors; Tritium - metabolism
• ISSN: 0953-816X; 1460-9568
• DOI: 10.1111/j.1460-9568.2004.03613.x

Cysteinyl‐leukotrienes (cys‐LTs), potent mediators in inflammatory diseases, are produced by nervous tissue, but their cellular source and role in the brain are not very well known. In this report we have demonstrated that rat cultured astrocytes express the enzymes (5′‐lipoxygenase and LTC4 synthase) required for cys‐LT production, and release cys‐LTs in resting condition and, to a greater extent, in response to calcium ionophore A23187, 1 h combined oxygen–glucose deprivation or 2‐methyl‐thioATP, a selective P2Y1/ATP receptor agonist. MK‐886, a LT synthesis inhibitor, prevented basal and evoked cys‐LT release. In addition, 2‐methyl‐thioATP‐induced cys‐LT release was abolished by suramin, a P2 receptor antagonist, or by inhibitors of ATP binding cassette proteins involved in cys‐LT release. We also showed that astrocytes express cys‐LT1 and not cys‐LT2 receptors. The stimulation of these receptors by LTD4 activated the mitogen‐activated protein kinase (MAPK) pathway. This effect was: (i) insensitive to inhibitors of receptor‐coupled Gi protein (pertussis toxin) or tyrosine kinase receptors (genistein); (ii) abolished by MK‐571, a cys‐LT1 selective receptor antagonist, or PD98059, a MAPK inhibitor; (iii) reduced by inhibitors of calcium/calmodulin‐dependent kinase II (KN‐93), Ca2+‐dependent and ‐independent (GF102903X) or Ca2+‐dependent (Gö6976) protein kinase C isoforms. LTD4 also increased astrocyte proliferation and glial fibrillary acidic protein content, which are considered hallmarks of reactive astrogliosis. Both effects were counteracted by cell pretreatment with MK‐571 or PD98059. Thus, cys‐LTs released from astrocytes might play an autocrine role in the induction of reactive astrogliosis that, in brain injuries, contributes to the formation of a reparative glial scar.