Resistance to endotoxic shock as a consequence of defective NF-κB 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-kappa B-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-KB 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 NE-kappa B-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. viva between PARP-1 and NF-KB, with consequences for the transcriptional activation of NF-kappa B and a systemic inflammatory process.