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.

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.