Journal
FASEB JOURNAL
Volume 26, Issue 7, Pages 3075-3083Publisher
FEDERATION AMER SOC EXP BIOL
DOI: 10.1096/fj.11-200279
Keywords
PGE(2); EP1; FP; TP; Parkinson's disease
Categories
Funding
- U.S. National Institutes of Health [ES16754, NS62864, AG35681, AG00258, DK37097, GM15431]
- Nancy and Buster Alvord Endowment
Ask authors/readers for more resources
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: similar to 60% enhancement by blocking or ablating of PGE(2) receptor subtype 1 (EP1), similar to 30% enhancement by activating PGF(2 alpha) receptor or thromboxane receptor, or similar to 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.-Li, X., Cudaback, E., Breyer, R. M., Montine, K. S., Keene, C. D., Montine, T. J. Eicosanoid receptor subtype-mediated opposing regulation of Toll-like receptor-stimulated expression of astrocyte glial-derived neurotrophic factor. FASEB J. 26, 3075-3083 (2012). www.fasebj.org
Authors
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available