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The 15-Deoxy-^12,14-Prostaglandin J₂ Suppresses Monocyte Chemoattractant Protein-1 Expression in IFN--Stimulated Astrocytes through Induction of MAPK Phosphatase-1¹

Department of Pharmacology, Chronic Inflammatory Disease Research Center, Ajou University School of Medicine, Suwon, Korea

The 15-deoxy-^12,14-PGJ₂ (15d-PGJ₂) is a cyclopentene PG generated from PGD₂. It is an endogenous ligand of the peroxisome proliferator-activated receptor- 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-PGJ₂ 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-PGJ₂ suppressed MCP-1 transcription and protein secretion in IFN--stimulated brain astrocytes. The inhibitory effects of 15d-PGJ₂ on MCP-1 resulted from its actions on the transcription factors, AP-1 and specificity protein-1, which play key roles in IFN--induced MCP-1 expression in astrocytes. Of interest, the negative effects of 15d-PGJ₂ 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-PGJ₂ in a peroxisome proliferator-activated receptor-independent manner. Thus, our data demonstrate a novel anti-inflammatory mechanism of 15d-PGJ₂ involving MKP-1. Considering the importance of MCP-1 in inflammatory processes, our results suggest that 15d-PGJ₂ analogues may have therapeutic potential to attenuate inflammatory brain diseases by inducing MKP-1 expression.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by a Korea Science and Engineering Foundation grant funded by the Korea government (Ministry of Science and Technology; R13-2003-019).

² Address correspondence and reprint requests to Dr. Ilo Jou, Department of Pharmacology, Chronic Inflammatory Disease Research Center, Ajou University School of Medicine, Suwon, 442-721, Korea. E-mail address: jouilo{at}ajou.ac.kr

³ Abbreviations used in this paper: 15d-PGJ₂, 15-deoxy-^12,14-PGJ₂; ChIP, chromatin immunoprecipitation; MKP, MAPK phosphatase; PP, protein phosphatase; PPAR, peroxisome proliferator-activated receptor; siRNA, small interfering RNA; Sp, specificity protein.