title: The anti-inflammatory role of extranuclear apurinic/apyrimidinic endonuclease 1/redox effector factor-1 in reactive astrocytes.
abstract: Apurinic/apyrimidinic endonuclease 1 (APE1), a ubiquitous multipurpose protein, is also known as redox effector factor-1 (Ref-1). It is involved in DNA repair and redox signaling and, in turn, oxidative stress-induced neurodegeneration. Although previous studies have demonstrated that APE1/Ref-1 functions as a negative regulator of inflammatory response via several mechanisms in neuronal cells, little is known about the roles of APE1/Ref-1 in glial cells. In this study, we found that cytoplasmic APE1/Ref-1 expression was upregulated in reactive astrocytes of the kainic acid- or lipopolysaccharide (LPS)-injected hippocampus. Analysis of the inflammatory response induced by extranuclear APE1/Ref-1 (ΔNLS-Ref-1) in cultured primary astrocytes revealed that it markedly suppressed inducible nitric oxide synthase (iNOS) expression and tumor necrosis factor-α (TNF-α) secretion induced by LPS to a similar extent as did wild type APE1/Ref-1 (WT-Ref-1), supporting the concept an anti-inflammatory role of extranuclear APE1/Ref-1 in astrocytes. Additionally, overexpression of WT- and ΔNLS-Ref-1 suppressed the transcriptional activity of nuclear factor-κB (NF-κB), although it effectively enhanced activator protein 1 (AP-1) activity. The blunting effect of APE1/Ref-1 on LPS-induced NF-κB activation was not mediated by IκB kinase (IKK) activity. Instead, APE1/Ref-1 inhibited p300-mediated acetylation of p65 by suppressing intracellular reactive oxygen species (ROS) levels following LPS treatment. Taken together, our results showed that altered expression and/or subcellular distribution of APE1/Ref-1 in activated astrocytes regulated the neuroinflammatory response to excitotoxin and endotoxin insults used in model of neurodegenerative brain diseases.
authors.affiliation: Department of Physiology and Department of Medical Science, School of Medicine, Chungnam National University, 266 Munhwa-Ro, Jung-gu, Daejeon, 30501, Republic of Korea.
authors.forename: Hyunjung
authors.initials: H
authors.lastname: Baek
authors.affiliation: Department of Anesthesiology & Pain Medicine, School of Medicine, Chungnam National University, Daejeon, 30501, Republic of Korea.
authors.forename: Chae Seong
authors.initials: CS
authors.lastname: Lim
authors.affiliation: Department of Pharmacology, School of Medicine, Chungnam National University, Daejeon, 30501, Republic of Korea.
authors.forename: Hee Sun
authors.initials: HS
authors.lastname: Byun
authors.affiliation: Department of Physiology and Department of Medical Science, School of Medicine, Chungnam National University, 266 Munhwa-Ro, Jung-gu, Daejeon, 30501, Republic of Korea.
authors.forename: Hyun Sil
authors.initials: HS
authors.lastname: Cho
authors.affiliation: Department of Physiology and Department of Medical Science, School of Medicine, Chungnam National University, 266 Munhwa-Ro, Jung-gu, Daejeon, 30501, Republic of Korea.
authors.forename: Yu Ran
authors.initials: YR
authors.lastname: Lee
authors.affiliation: Department of Anesthesiology & Pain Medicine, School of Medicine, Chungnam National University, Daejeon, 30501, Republic of Korea.
authors.forename: Yong Sup
authors.initials: YS
authors.lastname: Shin
authors.affiliation: Department of Physiology and Department of Medical Science, School of Medicine, Chungnam National University, 266 Munhwa-Ro, Jung-gu, Daejeon, 30501, Republic of Korea.
authors.forename: Hyun-Woo
authors.initials: HW
authors.lastname: Kim
authors.affiliation: Department of Physiology and Department of Medical Science, School of Medicine, Chungnam National University, 266 Munhwa-Ro, Jung-gu, Daejeon, 30501, Republic of Korea.
authors.forename: Byeong Hwa
authors.initials: BH
authors.lastname: Jeon
authors.affiliation: Department of Anatomy and Department of Medical Science, School of Medicine, Chungnam National University, Daejeon, 30501, Republic of Korea.
authors.forename: Dong Woon
authors.initials: DW
authors.lastname: Kim
authors.affiliation: Department of Anatomy and Department of Medical Science, School of Medicine, Chungnam National University, Daejeon, 30501, Republic of Korea.
authors.forename: Jinpyo
authors.initials: J
authors.lastname: Hong
authors.affiliation: Department of Pharmacology, School of Medicine, Chungnam National University, Daejeon, 30501, Republic of Korea. gmhur@cnu.ac.kr.
authors.forename: Gang Min
authors.initials: GM
authors.lastname: Hur
authors.affiliation: Department of Physiology and Department of Medical Science, School of Medicine, Chungnam National University, 266 Munhwa-Ro, Jung-gu, Daejeon, 30501, Republic of Korea. jinbong@cnu.ac.kr.
authors.forename: Jin Bong
authors.identifier: 0000-0002-0081-945X
authors.initials: JB
authors.lastname: Park
mesh_terms: D000107:Acetylation; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000378:metabolism*; D001253:Astrocytes / Q000378:metabolism*; D002478:Cells, Cultured; D003593:Cytoplasm / Q000201:enzymology; D043603:DNA-(Apurinic or Apyrimidinic Site) Lyase / Q000378:metabolism*; D050881:E1A-Associated p300 Protein / Q000378:metabolism; D006624:Hippocampus / Q000473:pathology; D006801:Humans; D051550:I-kappa B Kinase / Q000378:metabolism; D007249:Inflammation / Q000473:pathology; D007608:Kainic Acid; D008070:Lipopolysaccharides; D052247:Nitric Oxide Synthase Type II / Q000378:metabolism; D021381:Protein Transport; D051381:Rats; D017382:Reactive Oxygen Species / Q000378:metabolism; D017384:Sequence Deletion; D015398:Signal Transduction; D013347:Subcellular Fractions / Q000378:metabolism; D051996:Transcription Factor RelA / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
chemical_list: D000893:Anti-Inflammatory Agents; D008070:Lipopolysaccharides; D017382:Reactive Oxygen Species; D051996:Transcription Factor RelA; D014409:Tumor Necrosis Factor-alpha; D052247:Nitric Oxide Synthase Type II; D050881:E1A-Associated p300 Protein; C494362:Ep300 protein, rat; D051550:I-kappa B Kinase; C470319:Apex1 protein, rat; D043603:DNA-(Apurinic or Apyrimidinic Site) Lyase; D007608:Kainic Acid
keywords: APE1/Ref-1; Astrocytes; Inflammation; TNF-α; iNOS