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Resistance to endotoxic shock as a consequence of defective NF‐κB activation in poly (ADP‐ribose) polymerase‐1 deficient mice
Author(s) -
Oliver F.Javier,
Ménissierde Murcia Josiane,
Nacci Carmela,
Decker Patrice,
Andriantsitohaina Ramaroson,
Muller Sylviane,
de la Rubia Guadalupe,
Claude Stoclet Jean,
de Murcia Gilbert
Publication year - 1999
Publication title -
the embo journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 7.484
H-Index - 392
eISSN - 1460-2075
pISSN - 0261-4189
DOI - 10.1093/emboj/18.16.4446
Subject(s) - poly adp ribose polymerase , biology , microbiology and biotechnology , nfkb1 , nitric oxide synthase , polymerase , transcription (linguistics) , lipopolysaccharide , tumor necrosis factor alpha , nitric oxide , nf κb , dna damage , dna repair , parp inhibitor , inflammation , transcription factor , dna , biochemistry , immunology , gene , endocrinology , linguistics , philosophy
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.