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5, 8, 11, 14-eicosatetraynoic acid suppresses CCL2/MCP-1 expression in IFN-γ-stimulated astrocytes by increasing MAPK phosphatase-1 mRNA stability

Authors
Lee, JH; Kim, H; Woo, JH; Joe, EH; Jou, I
Citation
Journal of neuroinflammation, 9:34-34, 2012
Journal Title
Journal of neuroinflammation
ISSN
1742-2094
Abstract
BACKGROUND: The peroxisome proliferator-activated receptor (PPAR)-α activator, 5,8,11,14-eicosatetraynoic acid (ETYA), is an arachidonic acid analog. It is reported to inhibit up-regulation of pro-inflammatory genes; however, its underlying mechanism of action is largely unknown. In the present study, we focused on the inhibitory action of ETYA on the expression of the chemokine, CCL2/MCP-1, which plays a key role in the initiation and progression of inflammation.



METHODS: To determine the effect of ETYA, primary cultured rat astrocytes and microglia were stimulated with IFN-γ in the presence of ETYA and then, expression of CCL2/MCP-1 and MAPK phosphatase (MKP-1) were determined using RT-PCR and ELISA. MKP-1 mRNA stability was evaluated by treating actinomycin D. The effect of MKP-1 and human antigen R (HuR) was analyzed by using specific siRNA transfection system. The localization of HuR was analyzed by immunocytochemistry and subcellular fractionation experiment.



RESULTS: We found that ETYA suppressed CCL2/MCP-1 transcription and secretion of CCL2/MCP-1 protein through up-regulation of MKP-1mRNA levels, resulting in suppression of c-Jun N-terminal kinase (JNK) phosphorylation and activator protein 1 (AP1) activity in IFN-γ-stimulated brain glial cells. Moreover, these effects of ETYA were independent of PPAR-α. Experiments using actinomycin D revealed that the ETYA-induced increase in MKP-1 mRNA levels reflected an increase in transcript stability. Knockdown experiments using small interfering RNA demonstrated that this increase in MKP-1 mRNA stability depended on HuR, an RNA-binding protein known to promote enhanced mRNA stability. Furthermore, ETYA-induced, HuR-mediated mRNA stabilization resulted from HuR-MKP-1 nucleocytoplasmic translocation, which served to protect MKP-1 mRNA from the mRNA degradation machinery.



CONCLUSION: ETYA induces MKP-1 through HuR at the post-transcriptional level in a receptor-independent manner. The mechanism revealed here suggests eicosanoids as potential therapeutic modulators of inflammation that act through a novel target.
MeSH terms
5,8,11,14-Eicosatetraynoic Acid/*pharmacologyAnimalsAnimals, NewbornAstrocytes/*drug effectsCells, CulturedCerebral Cortex/cytologyChemokine CCL2/*metabolismChromatin ImmunoprecipitationDual Specificity Phosphatase 1/*geneticsElectrophoretic Mobility Shift AssayEnzyme Inhibitors/pharmacologyEnzyme-Linked Immunosorbent Assay/methodsGene Expression Regulation, Enzymologic/drug effectsHu Paraneoplastic Encephalomyelitis AntigensHumansInterferon-gamma/*pharmacologyMicroglia/drug effectsRNA, Messenger/*metabolismRNA, Small Interfering/genetics/metabolismRatsRats, Sprague-DawleyTransfection
DOI
10.1186/1742-2094-9-34
PMID
22339770
Appears in Collections:
Journal Papers > Research Organization > Chronic Inflammatory Disease Research Center
Journal Papers > School of Medicine / Graduate School of Medicine > Pharmacology
AJOU Authors
이, 지훈우, 주홍조, 은혜주, 일로
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