PPARalpha ligands inhibit radiation-induced microglial inflammatory responses by negatively regulating NF-kappaB and AP-1 pathways.
Whole-brain irradiation (WBI) can lead to cognitive impairment several months to years after irradiation. Studies on rodents have shown a rapid and sustained increase in activated microglia (brain macrophages) following brain irradiation, contributing to a chronic inflammatory response and a corresponding decrease in hippocampal neurogenesis. Thus, alleviating microglial activation following radiation represents a key strategy to minimize WBI-induced morbidity. We hypothesized that pretreatment with peroxisomal proliferator-activated receptor (PPAR)alpha agonists would ameliorate the proinflammatory responses seen in the microglia following in vitro radiation. Irradiating BV-2 cells (a murine microglial cell line) with single doses (2-10 Gy) of (137)Cs gamma-rays led to increases in (1) the gene expression of IL-1beta and TNFalpha, (2) Cox-2 protein levels, and (3) intracellular ROS generation. In addition, an increase in the DNA-binding activity of redox-regulated proinflammatory transcription factors AP-1 and NF-kappaB was observed. Pretreating BV-2 cells with the PPARalpha agonists GW7647 and Fenofibrate significantly inhibited the radiation-induced microglial proinflammatory response, in part, via decreasing (i) the nuclear translocation of the NF-kappaB p65 subunit and (ii) phosphorylation of the c-jun subunit of AP-1 in the nucleus. Taken together, these data support the hypothesis that activation of PPARalpha can modulate the radiation-induced microglial proinflammatory response.
Department of Cancer Biology, Comprehensive Cancer Center, Wake Forest University School of Medicine, Winston-Salem, NC 27157, USA.
Sriram
S
Ramanan
Mitra
M
Kooshki
Weiling
W
Zhao
Fang-Chi
FC
Hsu
Mike E
ME
Robbins
D000818:Animals; D002087:Butyrates / Q000494:pharmacology*; D002467:Cell Nucleus / Q000378:metabolism; D002478:Cells, Cultured; D051546:Cyclooxygenase 2 / Q000378:metabolism; D024202:Electrophoretic Mobility Shift Assay; D011345:Fenofibrate / Q000494:pharmacology*; D005720:Gamma Rays; D005786:Gene Expression Regulation / Q000502:physiology / Q000528:radiation effects; D000960:Hypolipidemic Agents / Q000494:pharmacology; D015151:Immunoblotting; D053583:Interleukin-1beta / Q000378:metabolism; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D008156:Luciferases / Q000378:metabolism; D051379:Mice; D017628:Microglia / Q000276:immunology / Q000378:metabolism / Q000528:radiation effects*; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism*; D047493:PPAR alpha / Q000819:agonists / Q000235:genetics / Q000378:metabolism*; D010671:Phenylurea Compounds / Q000494:pharmacology*; D010766:Phosphorylation / Q000528:radiation effects; D021381:Protein Transport; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D018808:Transcription Factor AP-1 / Q000235:genetics / Q000378:metabolism*; D014158:Transcription, Genetic / Q000528:radiation effects; D015533:Transcriptional Activation; D014162:Transfection; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
D002087:Butyrates; C453899:GW 7647; D000960:Hypolipidemic Agents; D053583:Interleukin-1beta; D016328:NF-kappa B; D047493:PPAR alpha; D010671:Phenylurea Compounds; D012333:RNA, Messenger; D017382:Reactive Oxygen Species; D018808:Transcription Factor AP-1; D014409:Tumor Necrosis Factor-alpha; D008156:Luciferases; C077623:Ptgs2 protein, mouse; D051546:Cyclooxygenase 2; D048031:JNK Mitogen-Activated Protein Kinases; D011345:Fenofibrate