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

Poly (ADP-ribose) polymerase-1 is a nuclear DNA-binding protein that partic ipates in the DNA base excision repair pathway in response to genotoxic str ess in mammalian cells. Here we show that PARP-1-deficient cells are defect ive in NF-kappa B-dependent transcription activation, but not in its nuclea r translocation, in response to TNF-alpha, Treating mice with lipopolysacch aride (LPS) resulted in the rapid activation of NF-KB in macrophages from P ARP-1(+/+) but not from PARP-1(-/-) mice, PARP-1-deficient mice were extrem ely 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 n itric oxide synthase (INOS), leading to decreased NO synthesis, which is th e main source of free radical generation during inflammation. These results demonstrate a functional association in. viva between PARP-1 and NF-KB, wi th consequences for the transcriptional activation of NF-kappa B and a syst emic inflammatory process.