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PGE2 Inhibits IL-10 Production via EP2-Mediated ?-Arrestin Signaling in Neuroinflammatory Condition.

ABSTRACT: 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-? (TNF-?), 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-?, IL-1?, 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-?, 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-? and PGE2. Further studies showed that negative regulation of IL-10 production by TNF-? 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 ?-arrestin-1 or ?-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 ?-arrestin-dependent signaling pathway.

SUBMITTER: Chu CH

PROVIDER: S-EPMC4362923 | biostudies-literature | 2015 Aug

REPOSITORIES: biostudies-literature

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PGE2 Inhibits IL-10 Production via EP2-Mediated β-Arrestin Signaling in Neuroinflammatory Condition.

Chu Chun-Hsien CH Chen Shih-Heng SH Wang Qingshan Q Langenbach Robert R Li Hong H Zeldin Darryl D Chen Shiou-Lan SL Wang Shijun S Gao Huiming H Lu Ru-Band RB Hong Jau-Shyong JS

Molecular neurobiology 20140914 1

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, an ...[more]

PMID: 25218510

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Project description:BackgroundNeuroinflammation has recently emerged as a critical risk factor in the pathophysiology of depression. However, the underlying molecular mechanisms and the development of novel therapeutic strategies as means to target these inflammatory pathways for use in the treatment of depression remain unresolved. In the present study, we aimed to investigate the molecular events of neuroinflammation as related to its induction of depression-like behaviors.MethodsChronic unpredictable mild stress (CUMS) or lipopolysaccharide (LPS) was used to induce depression-like behaviors in rats. The inflammatory factors and related proteins were verified by RT-PCR, immunoblotting, and immunofluorescence assay. In vivo intracerebral injection of adenovirus-associated virus (AAV) in rats was used to overexpress or block the function of the β form of the calcium/calmodulin-dependent protein kinase type II (βCaMKII). In vivo intracerebroventricular injection of SB203580 was used to block p38 mitogen-activated protein kinase (MAPK). Finally, the prostaglandin E2 (PGE2) concentration was verified by using enzyme-linked assay kit.ResultsThe expression of cyclo-oxygenase (COX)-2, which is responsible for production of the pro-inflammatory factor PGE2 and thus glial activation, was increased in the CA1 hippocampus in a rat model of depression. Further, the βCaMKII in CA1 was significantly upregulated in depressed rats, while antidepressant treatment downregulated this kinase. Overexpression of βCaMKII via infusion of a constructed AAV-βCaMKII into the CA1 region resulted in phosphorylation of the p38 MAPK and the activating transcription factor 2 (ATF2). These effects were accompanied by an enhanced activity of the COX-2/PGE2 pathway and effectively induced core symptoms of depression. Conversely, knockdown of βCaMKII within the CA1 region reversed these inflammation-related biochemical parameters and significantly rescued depression symptoms.ConclusionThese results demonstrate that βCaMKII can act as a critical regulator in depression via activating neuroinflammatory pathways within the CA1 region. Moreover, this study provides new perspectives on molecular targets and drug therapies for future investigation in the treatment of depression.

Dataset Information

PGE2 Inhibits IL-10 Production via EP2-Mediated ?-Arrestin Signaling in Neuroinflammatory Condition.

Publications

PGE2 Inhibits IL-10 Production via EP2-Mediated β-Arrestin Signaling in Neuroinflammatory Condition.

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