Eicosanoid receptor subtype-mediated opposing regulation of TLR-stimulated expression of astrocyte glial-derived neurotrophic factor.

Li X, Cudaback E, Breyer RM, Montine KS, Keene CD, Montine TJ
FASEB J. 2012 26 (7): 3075-83

PMID: 22499581 · PMCID: PMC3382097 · DOI:10.1096/fj.11-200279

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.

MeSH Terms (18)

Animals Astrocytes Base Sequence Cells, Cultured DNA Primers Glial Cell Line-Derived Neurotrophic Factor Immunity, Innate Mice Mice, Inbred C57BL Mice, Knockout Models, Biological Receptors, Eicosanoid Receptors, Prostaglandin E, EP1 Subtype Toll-Like Receptor 2 Toll-Like Receptor 3 Toll-Like Receptor 4 Toll-Like Receptor 9 Toll-Like Receptors

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