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A Study on the Effect of Peroxisome Proliferator-Activated Receptors (PPARs) Activation in Cultured Rat Brain Glial Cells

Other Title
신경 교세포에서 Peroxisome Proliferator-Activated Receptors (PPARs)의 작용기전과 효과에 대한 연구
Authors
이, 지훈
Degree
Doctor (2007)
Abstract
"The peroxisome proliferator-activated receptors (PPARs) are nuclear receptors, which were originally known to be involved in the regulation of lipid and glucose homeostasis. Recently, there has been increasing reports on the involvement of PPARs during inflammatory process, but the exact mechanisms of action are largely unknown. In this study, we tested the role of PPARs, PPAR-? and -?, on the development of LPS- and IFN-?-mediated inflammation in cultured rat brain glial cell.

In LPS-stimulated rat glial cells, we observed activators of PPAR-? inhibited pro-inflammatory mediators, including tumor necrosis factor-alpha (TNF-?), interleukin-6 (IL-6), interleukin-1 beta (IL-1?) and monocyte chemoattractant proteins (MCP-1) through suppressing activation of STAT1. Along with LPS, we further investigated whether activators of PPAR-? and -? also suppressed expression of pro-inflammatory mediators in IFN-?-activated rat astrocytes. Activators of PPAR-? inhibited pro-inflammatory mediators we also tested, including TNF-?, IL-6, and MCP-1. In contrast, those of PPAR-? could not suppress the expressions and release of MCP-1. Since several transcription factors, including NF-?B, C/EBP, STAT and AP-1/SP-1, were involved in its expression, we tested which plays a key role in among them. Sequential deletion of promoters revealed that AP-1/SP-1 act as key players, which were further confirmed by chromatin immunoprecipitation (ChIP). In an experiment to further reveal the mechanisms involved, we found that the differential effects on AP-1/SP-1 were mediated by Jun N-terminal kinase (JNK) and MAP kinase phosphatase-1 (MKP-1), upstream molecules of them. Taken together, these results show that signaling of MCP-1 expression differ from stimulus, such as LPS and IFN-?, and their production was differentially regulated by activators of PPAR-? and ??, which were ascribed to their effects on AP-1/SP-1, JNK and MKP-1, explaining more potent anti-inflammtory effects of PPAR-? than -? activators.

"
Keywords
PPAR-gammaPPAR-alphaMCP-1AP-1SP-1MKP-1LPSIFN-gamma
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Theses > School of Medicine / Graduate School of Medicine > Doctor
AJOU Authors
이, 지훈
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