Molecular neurobiologySep 15, 2014

PGE2 may reduce IL-10 production through EP2 receptor signaling involving β-arrestin in brain inflammation

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Updated Mar 31, 2026

Abstract

Lipopolysaccharide (LPS) exposure in brain cell cultures resulted in a sequential expression of inflammatory factors, with IL-10 being expressed last.

LPS triggered the expression of immune factors in the order of tumor necrosis factor-α (TNF-α), cyclooxygenase-2 (COX-2), and prostaglandin E2 (PGE2) before IL-10.
Microglia were identified as the primary producers of these inflammatory mediators.
Removing LPS from cultures was necessary for maintaining IL-10 expression, indicating that LPS presence is crucial.
Genetic disruption of TNF-α, its receptors, and COX-2 increased IL-10 production, suggesting that these factors negatively regulate IL-10 induction.
PGE2 was found to mediate the negative regulation of IL-10 production by TNF-α.
PGE2's suppression of IL-10 was linked to the EP2 receptor and required β-arrestin proteins, indicating a specific signaling pathway.

Simplified

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-α (TNF-α), cyclooxygenase-2 (COX-2), prostaglandin E2 (PGE2), 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-α, IL-1β, or PGE2) 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-α, 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-α and PGE2. Further studies showed that negative regulation of IL-10 production by TNF-α is mediated by PGE2. Mechanistic studies indicated that PGE2-elicited suppression of IL-10 induction was eliminated by genetic disruption of the PGE2 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 PGE2-mediated inhibition of IL-10 production, suggesting that a G protein-independent pathway was involved. Indeed, deficiency in β-arrestin-1 or β-arrestin-2 abolished PGE2-elicited suppression of IL-10 production. In conclusion, we have demonstrated that COX-2-derived PGE2 inhibits IL-10 expression in brain microglia through a novel EP2- and β-arrestin-dependent signaling pathway.

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PGE2 may reduce IL-10 production through EP2 receptor signaling involving β-arrestin in brain inflammation

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