title: Eicosanoid receptor subtype-mediated opposing regulation of TLR-stimulated expression of astrocyte glial-derived neurotrophic factor.
abstract: A major therapeutic target for Parkinson's disease (PD) is providing increased glial-derived neurotrophic factor (GDNF) to dopaminergic neurons. We tested the hypothesis that innate immune activation increases astrocyte GDNF production and that this is regulated by specific eicosanoid receptors. Innate immune-activated primary murine astrocytes were assayed for GDNF expression and secretion. Controls were agent vehicle exposure and wild-type mice. Rank order for up to 10-fold selectively increased GDNF expression was activators of TLR3 > TLR2 or TLR4 > TLR9. TLR3 activator-stimulated GDNF expression was selectively JNK-dependent, followed cyclooxygenase (COX)-2, was coincident with membranous PGE(2) synthase, and was not significantly altered by a nonspecific COX- or a COX-2-selective inhibitor. Specific eicosanoid receptors had opposing effects on TLR3 activator-induced GDNF expression: ∼60% enhancement by blocking or ablating of PGE(2) receptor subtype 1 (EP1), ∼30% enhancement by activating PGF(2α) receptor or thromboxane receptor, or ∼15% enhancement by activating EP4. These results demonstrate functionally antagonistic eicosanoid receptor subtype regulation of innate immunity-induced astrocyte GDNF expression and suggest that selective inhibition of EP1 signaling might be a means to augment astrocyte GDNF secretion in the context of innate immune activation in diseased regions of brain in PD.
authors.affiliation: Department of Pathology, University of Washington, Box 359645, Seattle, WA 98104, USA. xli@u.washington.edu
authors.forename: Xianwu
authors.initials: X
authors.lastname: Li
authors.forename: Eiron
authors.initials: E
authors.lastname: Cudaback
authors.forename: Richard M
authors.initials: RM
authors.lastname: Breyer
authors.forename: Kathleen S
authors.initials: KS
authors.lastname: Montine
authors.forename: C Dirk
authors.initials: CD
authors.lastname: Keene
authors.forename: Thomas J
authors.initials: TJ
authors.lastname: Montine
mesh_terms: D000818:Animals; D001253:Astrocytes / Q000276:immunology / Q000378:metabolism*; D001483:Base Sequence; D002478:Cells, Cultured; D017931:DNA Primers / Q000235:genetics; D051100:Glial Cell Line-Derived Neurotrophic Factor / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D007113:Immunity, Innate; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008954:Models, Biological; D018055:Receptors, Eicosanoid / Q000145:classification / Q000378:metabolism*; D058306:Receptors, Prostaglandin E, EP1 Subtype / Q000378:metabolism; D051195:Toll-Like Receptor 2 / Q000378:metabolism; D051196:Toll-Like Receptor 3 / Q000378:metabolism; D051197:Toll-Like Receptor 4 / Q000378:metabolism; D051217:Toll-Like Receptor 9 / Q000378:metabolism; D051193:Toll-Like Receptors / Q000378:metabolism*
chemical_list: D017931:DNA Primers; C495040:Gdnf protein, mouse; D051100:Glial Cell Line-Derived Neurotrophic Factor; C545636:Ptger1 protein, mouse; D018055:Receptors, Eicosanoid; D058306:Receptors, Prostaglandin E, EP1 Subtype; C519703:TLR3 protein, mouse; C493486:Tlr2 protein, mouse; C493487:Tlr4 protein, mouse; C495370:Tlr9 protein, mouse; D051195:Toll-Like Receptor 2; D051196:Toll-Like Receptor 3; D051197:Toll-Like Receptor 4; D051217:Toll-Like Receptor 9; D051193:Toll-Like Receptors