Journal
MOLECULAR NEUROBIOLOGY
Volume 52, Issue 1, Pages 587-600Publisher
SPRINGER
DOI: 10.1007/s12035-014-8889-0
Keywords
Microglia; IL-10; PGE2; COX-2; EP2; beta-arrestin
Categories
Funding
- NIH/NIEHS [ES090082, ES025043]
- National Natural Science Foundation of China
- Jiangsu Province of China
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Regulatory mechanisms of the expression of interleukin-10 (IL-10) in brain inflammatory conditions remain elusive. To address this issue, we used multiple primary brain cell cultures to study the expression of IL-10 in lipopolysaccharide (LPS)-elicited inflammatory conditions. In neuron-glia cultures, LPS triggered well-orchestrated expression of various immune factors in the following order: tumor necrosis factor-alpha (TNF-alpha), cyclooxygenase-2 (COX-2), prostaglandin E2 (PGE(2)), and lastly IL-10, and these inflammatory mediators were mainly produced from microglia. While exogenous application of individual earlier-released pro-inflammatory factors (e.g., TNF-alpha, IL-1 beta, or PGE(2)) failed to induce IL-10 expression, removal of LPS from the cultures showed the requirement of continuing presence of LPS for IL-10 expression. Interestingly, genetic disruption of tnf-alpha, its receptors tnf-r1/r2, and cox-2 and pharmacological inhibition of COX-2 activity enhanced LPS-induced IL-10 production in microglia, which suggests negative regulation of IL-10 induction by the earlier-released TNF-alpha and PGE(2). Further studies showed that negative regulation of IL-10 production by TNF-alpha is mediated by PGE(2). Mechanistic studies indicated that PGE(2)-elicited suppression of IL-10 induction was eliminated by genetic disruption of the PGE(2) receptor EP2 and was mimicked by the specific agonist for the EP2, butaprost, but not agonists for the other three EP receptors. Inhibition of cAMP-dependent signal transduction failed to affect PGE(2)-mediated inhibition of IL-10 production, suggesting that a G protein-independent pathway was involved. Indeed, deficiency in beta-arrestin-1 or beta-arrestin-2 abolished PGE(2)-elicited suppression of IL-10 production. In conclusion, we have demonstrated that COX-2-derived PGE(2) inhibits IL-10 expression in brain microglia through a novel EP2- and beta-arrestin-dependent signaling pathway.
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