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The 15-deoxy-delta 12,14-prostaglandin J2 suppresses monocyte chemoattractant protein-1 expression in IFN-gamma-stimulated astrocytes through induction of MAPK phosphatase-1.

Authors
Lee, JH; Woo, JH; Woo, SU; Kim, KS; Park, SM; Joe, EH; Jou, I
Citation
Journal of immunology (Baltimore, Md. : 1950), 181(12):8642-8649, 2008
Journal Title
Journal of immunology (Baltimore, Md. : 1950)
ISSN
0022-17671550-6606
Abstract
The 15-deoxy-Delta(12,14)-PGJ(2) (15d-PGJ(2)) is a cyclopentene PG generated from PGD(2). It is an endogenous ligand of the peroxisome proliferator-activated receptor-gamma that is primarily involved in adipocyte differentiation and lipid metabolism. Its anti-inflammatory actions have recently attracted considerable research attention, although the precise role and underlying mechanisms of these actions are largely unknown. In the present study, we focused on the inhibitory action of 15d-PGJ(2) on the chemokine MCP-1, which plays a key role in the initiation and progression of inflammation by recruiting inflammatory cells to lesion sites. We found that 15d-PGJ(2) suppressed MCP-1 transcription and protein secretion in IFN-gamma-stimulated brain astrocytes. The inhibitory effects of 15d-PGJ(2) on MCP-1 resulted from its actions on the transcription factors, AP-1 and specificity protein-1, which play key roles in IFN-gamma-induced MCP-1 expression in astrocytes. Of interest, the negative effects of 15d-PGJ(2) on AP-1/specificity protein-1 signaling and the resulting inhibition of MCP-1 expression were mediated by MAPK phosphatase (MKP)-1 activity, which was induced by 15d-PGJ(2) in a peroxisome proliferator-activated receptor-independent manner. Thus, our data demonstrate a novel anti-inflammatory mechanism of 15d-PGJ(2) involving MKP-1. Considering the importance of MCP-1 in inflammatory processes, our results suggest that 15d-PGJ(2) analogues may have therapeutic potential to attenuate inflammatory brain diseases by inducing MKP-1 expression.
MeSH terms
AnimalsAstrocytes/enzymologyAstrocytes/immunology*Astrocytes/metabolism*Astrocytes/pathologyCells, CulturedChemokine CCL2/antagonists & inhibitors*Chemokine CCL2/biosynthesis*Chemokine CCL2/geneticsDown-Regulation/immunology*Dual Specificity Phosphatase 1/biosynthesis*Dual Specificity Phosphatase 1/geneticsDual Specificity Phosphatase 1/physiologyEncephalitis/enzymologyEncephalitis/immunologyEncephalitis/prevention & controlEnzyme Induction/immunologyInflammation Mediators/antagonists & inhibitorsInflammation Mediators/physiologyInterferon-gamma/physiology*Microglia/enzymologyMicroglia/immunologyMicroglia/pathologyPPAR gamma/physiologyProstaglandin D2/analogs & derivatives*Prostaglandin D2/physiologyRatsRats, Sprague-DawleySignal Transduction/immunologySp1 Transcription Factor/antagonists & inhibitorsSp1 Transcription Factor/physiologyTranscription Factor AP-1/antagonists & inhibitorsTranscription Factor AP-1/physiology
PMID
19050284
Appears in Collections:
Journal Papers > School of Medicine / Graduate School of Medicine > Pharmacology
Journal Papers > Research Organization > Chronic Inflammatory Disease Research Center
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