PPAR未 prevents radiation-induced proinflammatory responses in microglia via transrepression of NF-魏B and inhibition of the PKC伪/MEK1/2/ERK1/2/AP-1 pathway

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• 作者：Caroline I. Schnegg^a ; ^b ; Mitra Kooshki^b ; ^c ; Fang-Chi Hsu^d ; Guangchao Sui^a ; Mike E. Robbins^a ; ^b ; ^c ; ^{mrobbins@wakehealth.edu}
• 关键词：AP-1 ; activator protein-1 ; CNS ; central nervous system ; Cox-2 ; cyclooxygenase-2 ; ERK1/2 ; extracellular signal-related kinase 1/2 ; ICAM-1 ; intracellular cellular adhesion molecule-1 ; IL-1尾 ; interleukin-1尾 ; MCP-1 ; monocyte chemoattractant protein-1 ; MEK1/
• 刊名：Free Radical Biology and Medicine
• 出版年：2012
• 期刊代码：105_08915849
• 类别：med
• 出版时间：1 May, 2012
• 卷：52
• 期：9
• 页码：1734-1743
• 文件大小：1293 K

摘要

Partial or whole-brain irradiation is often required to treat both primary and metastatic brain cancer. Radiation-induced normal tissue injury, including progressive cognitive impairment, however, can significantly affect the well-being of the approximately 200,000 patients who receive these treatments each year in the United States. Although the exact mechanisms underlying radiation-induced late effects remain unclear, oxidative stress and inflammation are thought to play a critical role. Microglia are key mediators of neuroinflammation. Peroxisomal proliferator-activated receptor (PPAR) 未 has been shown to be a potent regulator of anti-inflammatory responses. Thus, we hypothesized that PPAR未 activation would modulate the radiation-induced inflammatory response in microglia. Incubating BV-2 murine microglial cells with the PPAR未 agonist L-165041 prevented the radiation-induced increase in: (i) intracellular reactive oxygen species generation, (ii) Cox-2 and MCP-1 expression, and (iii) IL-1尾 and TNF-伪 message levels. This occurred, in part, through PPAR未-mediated modulation of stress-activated kinases and proinflammatory transcription factors. PPAR未 inhibited NF-魏B via transrepression by physically interacting with the p65 subunit and prevented activation of the PKC伪/MEK1/2/ERK1/2/AP-1 pathway by inhibiting the radiation-induced increase in intracellular reactive oxygen species generation. These data support the hypothesis that PPAR未 activation can modulate radiation-induced oxidative stress and inflammatory responses in microglia.