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.
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.
Lee
Jee Hoon
JH
Department of Pharmacology, Chronic Inflammatory Disease Research Center, Ajou University School of Medicine, Suwon, Korea.
Woo
Joo Hong
JH
Woo
Sang Uk
SU
Kim
Kwang Soo
KS
Park
Sang Myun
SM
Joe
Eun-hye
EH
Jou
Ilo
I
D000818:Animals; D001253:Astrocytes / Q000201:enzymology / Q000276:immunology* / Q000378:metabolism* / Q000473:pathology; D002478:Cells, Cultured; D018932:Chemokine CCL2 / Q000037:antagonists & inhibitors* / Q000096:biosynthesis* / Q000235:genetics; D015536:Down-Regulation / Q000276:immunology*; D054638:Dual Specificity Phosphatase 1 / Q000096:biosynthesis* / Q000235:genetics / Q000502:physiology; D004660:Encephalitis / Q000201:enzymology / Q000276:immunology / Q000517:prevention & control; D004790:Enzyme Induction / Q000276:immunology; D018836:Inflammation Mediators / Q000037:antagonists & inhibitors / Q000502:physiology; D007371:Interferon-gamma / Q000502:physiology*; D017628:Microglia / Q000201:enzymology / Q000276:immunology / Q000473:pathology; D047495:PPAR gamma / Q000502:physiology; D015230:Prostaglandin D2 / Q000031:analogs & derivatives* / Q000502:physiology; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction / Q000276:immunology; D016329:Sp1 Transcription Factor / Q000037:antagonists & inhibitors / Q000502:physiology; D018808:Transcription Factor AP-1 / Q000037:antagonists & inhibitors / Q000502:physiology
C097240:15-deoxy-delta(12,14)-prostaglandin J2; C491766:Ccl2 protein, rat; D018932:Chemokine CCL2; D018836:Inflammation Mediators; D047495:PPAR gamma; D016329:Sp1 Transcription Factor; D018808:Transcription Factor AP-1; D007371:Interferon-gamma; D054638:Dual Specificity Phosphatase 1; D015230:Prostaglandin D2