Resistance to endotoxic shock as a consequence of defective NF-κB activation in poly (ADP-ribose) polymerase-1 deficient mice

Authors

  • F.Javier Oliver,

    1. UPR 9003 du Centre National de la Recherche Scientifique, ‘Cancérogenèse et Mutagenèse Moléculaire et Structurale’, Laboratoire Conventionné du Commissariat à l'Energie Atomique, Ecole Supérieure de Biotechnologie de Strasbourg, Illkirch-Graffenstaden, France
    2. Present address: Unidad Mixta de Investigaciones Médicas, Hospital Clínico San Cecilio, Universidad de Granada, Granada, Spain
    Search for more papers by this author
  • Josiane Ménissier-de Murcia,

    1. UPR 9003 du Centre National de la Recherche Scientifique, ‘Cancérogenèse et Mutagenèse Moléculaire et Structurale’, Laboratoire Conventionné du Commissariat à l'Energie Atomique, Ecole Supérieure de Biotechnologie de Strasbourg, Illkirch-Graffenstaden, France
    Search for more papers by this author
  • Carmela Nacci,

    1. Pharmacologie et Physico-Chimie des Interactions Cellulaires et Moléculaires, Université Louis Pasteur de Strasbourg et CNRS (UMR, ex ERS653), Faculté de Pharmacie, Illkirch-Graffenstaden, France
    Search for more papers by this author
  • Patrice Decker,

    1. Institut de Biologie Moleculaire et cellulaire, UPR 9021 du CNRS, Strasbourg, France
    Search for more papers by this author
  • Ramaroson Andriantsitohaina,

    1. Pharmacologie et Physico-Chimie des Interactions Cellulaires et Moléculaires, Université Louis Pasteur de Strasbourg et CNRS (UMR, ex ERS653), Faculté de Pharmacie, Illkirch-Graffenstaden, France
    Search for more papers by this author
  • Sylviane Muller,

    1. Institut de Biologie Moleculaire et cellulaire, UPR 9021 du CNRS, Strasbourg, France
    Search for more papers by this author
  • Guadalupe de la Rubia,

    1. UPR 9003 du Centre National de la Recherche Scientifique, ‘Cancérogenèse et Mutagenèse Moléculaire et Structurale’, Laboratoire Conventionné du Commissariat à l'Energie Atomique, Ecole Supérieure de Biotechnologie de Strasbourg, Illkirch-Graffenstaden, France
    2. Present address: Unidad Mixta de Investigaciones Médicas, Hospital Clínico San Cecilio, Universidad de Granada, Granada, Spain
    Search for more papers by this author
  • Jean Claude Stoclet,

    1. Pharmacologie et Physico-Chimie des Interactions Cellulaires et Moléculaires, Université Louis Pasteur de Strasbourg et CNRS (UMR, ex ERS653), Faculté de Pharmacie, Illkirch-Graffenstaden, France
    Search for more papers by this author
  • Gilbert de Murcia

    Corresponding author
    1. UPR 9003 du Centre National de la Recherche Scientifique, ‘Cancérogenèse et Mutagenèse Moléculaire et Structurale’, Laboratoire Conventionné du Commissariat à l'Energie Atomique, Ecole Supérieure de Biotechnologie de Strasbourg, Illkirch-Graffenstaden, France
    Search for more papers by this author

Abstract

Poly (ADP-ribose) polymerase-1 is a nuclear DNA-binding protein that participates in the DNA base excision repair pathway in response to genotoxic stress in mammalian cells. Here we show that PARP-1-deficient cells are defective in NF-κB-dependent transcription activation, but not in its nuclear translocation, in response to TNF-α. Treating mice with lipopolysaccharide (LPS) resulted in the rapid activation of NF-κB in macrophages from PARP-1+/+ but not from PARP-1−/− mice. PARP-1-deficient mice were extremely resistant to LPS-induced endotoxic shock. The molecular basis for this resistance relies on an almost complete abrogation of NF-κB-dependent accumulation of TNF-α in the serum and a down-regulation of inducible nitric oxide synthase (iNOS), leading to decreased NO synthesis, which is the main source of free radical generation during inflammation. These results demonstrate a functional association in vivo between PARP-1 and NF-κB, with consequences for the transcriptional activation of NF-κB and a systemic inflammatory process.

Ancillary