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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

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dc.contributor.authorLee, JH-
dc.contributor.authorKim, H-
dc.contributor.authorWoo, JH-
dc.contributor.authorJoe, EH-
dc.contributor.authorJou, I-
dc.date.accessioned2013-04-25T03:43:14Z-
dc.date.available2013-04-25T03:43:14Z-
dc.date.issued2012-
dc.identifier.urihttp://repository.ajou.ac.kr/handle/201003/7981-
dc.description.abstractBACKGROUND: 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.
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dc.language.isoen-
dc.subject.MESH5,8,11,14-Eicosatetraynoic Acid-
dc.subject.MESHAnimals-
dc.subject.MESHAnimals, Newborn-
dc.subject.MESHAstrocytes-
dc.subject.MESHCells, Cultured-
dc.subject.MESHCerebral Cortex-
dc.subject.MESHChemokine CCL2-
dc.subject.MESHChromatin Immunoprecipitation-
dc.subject.MESHDual Specificity Phosphatase 1-
dc.subject.MESHElectrophoretic Mobility Shift Assay-
dc.subject.MESHEnzyme Inhibitors-
dc.subject.MESHEnzyme-Linked Immunosorbent Assay-
dc.subject.MESHGene Expression Regulation, Enzymologic-
dc.subject.MESHHu Paraneoplastic Encephalomyelitis Antigens-
dc.subject.MESHHumans-
dc.subject.MESHInterferon-gamma-
dc.subject.MESHMicroglia-
dc.subject.MESHRNA, Messenger-
dc.subject.MESHRNA, Small Interfering-
dc.subject.MESHRats-
dc.subject.MESHRats, Sprague-Dawley-
dc.subject.MESHTransfection-
dc.title5, 8, 11, 14-eicosatetraynoic acid suppresses CCL2/MCP-1 expression in IFN-γ-stimulated astrocytes by increasing MAPK phosphatase-1 mRNA stability-
dc.typeArticle-
dc.identifier.pmid22339770-
dc.identifier.urlhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC3308915/-
dc.contributor.affiliatedAuthor이, 지훈-
dc.contributor.affiliatedAuthor우, 주홍-
dc.contributor.affiliatedAuthor조, 은혜-
dc.contributor.affiliatedAuthor주, 일로-
dc.type.localJournal Papers-
dc.identifier.doi10.1186/1742-2094-9-34-
dc.citation.titleJournal of neuroinflammation-
dc.citation.volume9-
dc.citation.date2012-
dc.citation.startPage34-
dc.citation.endPage34-
dc.identifier.bibliographicCitationJournal of neuroinflammation, 9. : 34-34, 2012-
dc.identifier.eissn1742-2094-
dc.relation.journalidJ017422094-
Appears in Collections:
Journal Papers > Research Organization > Inflamm-aging Translational Research Center
Journal Papers > School of Medicine / Graduate School of Medicine > Pharmacology
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