Resistance to endotoxic shock as a consequence of defective NF-kappaB activation in poly (ADP-ribose) polymerase-1 deficient mice.
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-kappaB-dependent transcription activation, but not in its nuclear translocation, in response to TNF-alpha. Treating mice with lipopolysaccharide (LPS) resulted in the rapid activation of NF-kappaB 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-kappaB-dependent accumulation of TNF-alpha 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-kappaB, with consequences for the transcriptional activation of NF-kappaB and a systemic inflammatory process.
Oliver
F J
FJ
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 Strasbo.
Ménissier-de Murcia
J
J
Nacci
C
C
Decker
P
P
Andriantsitohaina
R
R
Muller
S
S
de la Rubia
G
G
Stoclet
J C
JC
de Murcia
G
G
D016475:3T3 Cells; D000818:Animals; D001011:Aorta; D001692:Biological Transport; D002467:Cell Nucleus / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D020672:I-kappa B Proteins; D015850:Interleukin-6 / Q000096:biosynthesis; D008070:Lipopolysaccharides / Q000378:metabolism / Q000494:pharmacology; D051379:Mice; D008810:Mice, Inbred C57BL; D000072000:NF-KappaB Inhibitor alpha; D016328:NF-kappa B / Q000378:metabolism*; D019001:Nitric Oxide Synthase / Q000096:biosynthesis / Q000235:genetics; D052247:Nitric Oxide Synthase Type II; D011065:Poly(ADP-ribose) Polymerases / Q000235:genetics / Q000502:physiology*; D012772:Shock, Septic / Q000276:immunology* / Q000503:physiopathology; D051996:Transcription Factor RelA; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology
D004268:DNA-Binding Proteins; D020672:I-kappa B Proteins; D015850:Interleukin-6; D008070:Lipopolysaccharides; D016328:NF-kappa B; C000606205:Nfkbia protein, mouse; D051996:Transcription Factor RelA; D014409:Tumor Necrosis Factor-alpha; D000072000:NF-KappaB Inhibitor alpha; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; C496317:Nos2 protein, mouse; D011065:Poly(ADP-ribose) Polymerases