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.

Elevation of Serum APE1/Ref-1 in Experimental Murine Myocarditis

“…Although the exact mechanism for translocated or secreted APE1/Ref-1 is not completely understood, a few studies suggested insights into its biological functions. Altered subcellular translocation of APE1/Ref-1 in activated astrocytes regulated anti-inflammatory events [ 24 ] and recombinant APE1/Ref-1 showed anti-inflammatory activity by suppressing pro-inflammatory molecules in endothelial cells [ 23 ]. Because APE1/Ref-1 is increased and activated under the conditions like reactive oxygen species, ischemia/reperfusion injury, hypoxia or inflammation, its elevation in myocarditis may be expected.…”

Accelerated degradation of cFLIPL and sensitization of the TRAIL DISC-mediated apoptotic cascade by pinoresinol, a lignan isolated from Rubia philippinensis

“…Cells were cultured in Dulbecco’s modified Eagle’s medium (DMEM) including 10% fetal bovine serum, 2 mmol/L glutamine and 100 U/mL penicillin/streptomycin. The normal primary astrocytes were prepared from the neonatal rats, as described previously 58 , and cultured in Minimum Essential Media (MEM) with 10% FBS, 2 mmol/L glutamine and 100 U/mL penicillin/ streptomycin.…”

Beneficial Impacts of Alpha-Eleostearic Acid from Wild Bitter Melon and Curcumin on Promotion of CDGSH Iron-Sulfur Domain 2: Therapeutic Roles in CNS Injuries and Diseases

“…Microglia provide neurotrophic support for neurons and mainly mediate immune responses to stabilize the CNS [ 16 ]. Astrocyte-mediated neuroprotection has been proposed to be due to the limitation of neuronal death from excitotoxins and oxidants [ 17 ], maintenance energy metabolism [ 18 ], and the regulation of osmolarity for volume control [ 19 ]. Under environmental insults in the CNS, beneficial phenotypes (anti-inflammation) of M2 microglia and A2 astrocytes can be excessively stimulated and potentially switched to detrimental phenotypes (pro-inflammation) (M1 or A1, respectively) [ 20 ].…”