Apurinic/Apyrimidinic Endonuclease 1 Regulates Inflammatory Response in Macrophages

• Published in: Anticancer research 2011-02, Vol.31 (2), p.379-385
• Main Authors: JEDINAK, Andrej, DUDHGAONKAR, Shailesh, KELLEY, Mark R, SLIVA, Daniel
• Format: Article
• Language: English
• Subjects: Animals; Anti-Inflammatory Agents, Non-Steroidal; Benzoquinones - pharmacology; Biological and medical sciences; Cells, Cultured; Cyclooxygenase 2 - biosynthesis; Dinoprostone - immunology; Dinoprostone - metabolism; DNA-(Apurinic or Apyrimidinic Site) Lyase - antagonists & inhibitors; DNA-(Apurinic or Apyrimidinic Site) Lyase - immunology; DNA-(Apurinic or Apyrimidinic Site) Lyase - metabolism; Lipopolysaccharides - pharmacology; Macrophages - drug effects; Macrophages - enzymology; Macrophages - immunology; Medical sciences; Mice; NF-kappa B - immunology; NF-kappa B - metabolism; Nitric Oxide - immunology; Nitric Oxide - metabolism; Nitric Oxide Synthase Type II - biosynthesis; Oxidation-Reduction; Propionates - pharmacology; Signal Transduction; Transcription Factor AP-1 - immunology; Transcription Factor AP-1 - metabolism; Tumor Necrosis Factor-alpha - biosynthesis; Tumors
• ISSN: 0250-7005; 1791-7530

The multi-functional apyrimidinic endonuclease 1/redox factor-1 (APE1/Ref-1) DNA repair and redox signaling protein has been shown to have a role in cancer growth and survival, however, little has been investigated concerning its role in inflammation. In this study, an APE1 redox-specific inhibitor (E3330) was used in lypopolysaccharide (LPS)-stimulated macrophages (RAW264.7). E3330 clearly suppressed secretion of inflammatory cytokines including tumor necrosis factor-α (TNF-α), interleukin (IL-6) and IL-12 and inflammatory mediators nitric oxide (NO) as well as prostaglandin E(2) (PGE(2)) from the LPS-stimulated RAW264.7 cells. These data were supported by the down-regulation of the LPS-dependent expression of inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) genes in the RAW264.7 cells. The effects of E3330 were mediated by the inhibition of transcription factors nuclear factor-κB (NF-κB) and activator protein 1 (AP-1) in the LPS-stimulated macrophages, both known targets of APE1. In conclusion, pharmacological inhibition of APE1 by E3330 suppresses inflammatory response in activated macrophages and can be considered as a novel therapeutic strategy for the inhibition of tumor-associated macrophages.