title: PPARδ prevents radiation-induced proinflammatory responses in microglia via transrepression of NF-κB and inhibition of the PKCα/MEK1/2/ERK1/2/AP-1 pathway.
abstract: 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) δ has been shown to be a potent regulator of anti-inflammatory responses. Thus, we hypothesized that PPARδ activation would modulate the radiation-induced inflammatory response in microglia. Incubating BV-2 murine microglial cells with the PPARδ 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-1β and TNF-α message levels. This occurred, in part, through PPARδ-mediated modulation of stress-activated kinases and proinflammatory transcription factors. PPARδ inhibited NF-κB via transrepression by physically interacting with the p65 subunit and prevented activation of the PKCα/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 PPARδ activation can modulate radiation-induced oxidative stress and inflammatory responses in microglia.
authors.affiliation: Department of Cancer Biology, Wake Forest School of Medicine, Winston-Salem, NC 27157, USA.
authors.forename: Caroline I
authors.initials: CI
authors.lastname: Schnegg
authors.forename: Mitra
authors.initials: M
authors.lastname: Kooshki
authors.forename: Fang-Chi
authors.initials: FC
authors.lastname: Hsu
authors.forename: Guangchao
authors.initials: G
authors.lastname: Sui
authors.forename: Mike E
authors.initials: ME
authors.lastname: Robbins
mesh_terms: D000818:Animals; D001483:Base Sequence; D015153:Blotting, Western; D002461:Cell Line, Transformed; D024202:Electrophoretic Mobility Shift Assay; D047468:Immunoprecipitation; D007249:Inflammation / Q000209:etiology / Q000517:prevention & control; D051379:Mice; D017628:Microglia / Q000378:metabolism / Q000473:pathology*; D016328:NF-kappa B / Q000037:antagonists & inhibitors*; D047494:PPAR delta / Q000502:physiology*; D016133:Polymerase Chain Reaction; D011494:Protein Kinases / Q000378:metabolism*; D012313:RNA / Q000235:genetics; D017382:Reactive Oxygen Species / Q000378:metabolism; D018808:Transcription Factor AP-1 / Q000037:antagonists & inhibitors*
chemical_list: D016328:NF-kappa B; D047494:PPAR delta; D017382:Reactive Oxygen Species; D018808:Transcription Factor AP-1; D012313:RNA; D011494:Protein Kinases