title: Phospholipase D is a target for inhibition of astroglial proliferation by ethanol.
abstract: The proliferation of astrocytes during early brain development is driven by growth factors and is accompanied by the activation of phospholipase D (PLD). Ethanol disrupts PLD signaling in astrocytes, a process which may contribute to delayed brain growth of fetuses exposed to alcohol during pregnancy. We here report that insulin-like growth factor 1 (IGF-1) is a strong mitogen for rat astrocytes (EC50 0.2 μg/ml) and a strong stimulator of astroglial PLD activity; both effects are inhibited by ethanol and 1-butanol, but not t-butanol, suggesting participation of PLD. Downregulation of PLD1 and exposure to the PLD1 inhibitor VU0359595 attenuated PLD activity and strongly reduced the mitogenic activity of serum and IGF-1. The PLD2 inhibitor VU0285655-1 also reduced PLD activity but had lesser effects on IGF-1-driven proliferation. PLD2 down-regulation affected serum - but not IGF-1-induced proliferation. In separate experiments, alcohol treatment of murine astrocytes taken from PLD-deficient animals revealed an insensitivity of PLD1(-/-) cells to 1-butanol whereas PLD2(-/-) cells were not affected. We conclude that astroglial proliferation induced by IGF-1 is critically dependent on the PLD signaling pathway, with a stronger contribution from PLD1 than PLD2. The teratogenic effects of ethanol may be explained, at least in part, by disruption of the IGF1-PLD signaling pathway.
authors.affiliation: Department of Pharmacology, College of Pharmacy, Biocenter N260, Goethe University, Max-von-Laue-Str. 9, 60438 Frankfurt am Main, Germany.
authors.forename: Ute
authors.initials: U
authors.lastname: Burkhardt
authors.affiliation: Department of Pharmacology, College of Pharmacy, Biocenter N260, Goethe University, Max-von-Laue-Str. 9, 60438 Frankfurt am Main, Germany.
authors.forename: Bartosch
authors.initials: B
authors.lastname: Wojcik
authors.affiliation: Department of Pharmacology, College of Pharmacy, Biocenter N260, Goethe University, Max-von-Laue-Str. 9, 60438 Frankfurt am Main, Germany.
authors.forename: Martina
authors.initials: M
authors.lastname: Zimmermann
authors.affiliation: Department of Pharmacology, College of Pharmacy, Biocenter N260, Goethe University, Max-von-Laue-Str. 9, 60438 Frankfurt am Main, Germany. Electronic address: Klein@em.uni-frankfurt.de.
authors.forename: Jochen
authors.initials: J
authors.lastname: Klein
mesh_terms: D020001:1-Butanol / Q000494:pharmacology; D000818:Animals; D001253:Astrocytes / Q000187:drug effects* / Q000378:metabolism; D049109:Cell Proliferation / Q000187:drug effects*; D002478:Cells, Cultured; D015536:Down-Regulation / Q000187:drug effects; D000431:Ethanol / Q000494:pharmacology*; D007334:Insulin-Like Growth Factor I / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008934:Mitogens / Q000378:metabolism; D010739:Phospholipase D / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013723:Teratogens / Q000494:pharmacology*; D020002:tert-Butyl Alcohol / Q000494:pharmacology
chemical_list: D008934:Mitogens; D013723:Teratogens; C548904:insulin-like growth factor-1, rat; D000431:Ethanol; D007334:Insulin-Like Growth Factor I; D020001:1-Butanol; C105606:phospholipase D2; D010739:Phospholipase D; C106801:phospholipase D1; D020002:tert-Butyl Alcohol
keywords: Alcohol; Astrocytes; Cell proliferation; Fetal alcohol syndrome; Insulin-like growth factor 1; Phospholipase D; siRNA