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

Abstract

Poly (ADP-ribose) polymerase-1 is a nuclear DNAbinding 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 downregulation 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.

Differential expression in lupus-associated IL-10 promoter single-nucleotide polymorphisms is mediated by poly(ADP-ribose) polymerase-1

“…Accordingly, pharmacological inhibition of PARP-1 has shown therapeutic efficacy in animal models of inflammation such as ischemia-reperfusion, 60 chronic colitis, 65 asthma, 66 autoimmune encephalomyelitis, 67 diabetes mellitus, 68 and PARP À/À mice are protected from endotoxic shock. 69,70 Interestingly, in an ovalbumin sensitization model of asthma in mice, inhibition of PARP-1 with the potent water soluble inhibitor PJ-34 reduced the number of inflammatory cells (especially of neutrophils) in the bronchoalveolar lavage fluid. Accompanying the reduction in cellular infiltration was the reduction in the production of inflammatory cytokines TNF-a, IL-12, and the chemokine MIP-1.…”

PARP-1 inhibition-induced activation of PI-3-kinase-Akt pathway promotes resistance to taxol

“…These processes are important in the survival of the cells after extensive DNA damage but in normal cells the complete absence of PARP-1 protein or the inhibition of PARP-1 catalytic activity produces no significant growth defect [33]. This is supported by the observation that PARP-1 defective mice survive and have no obvious growth defect [34]. However, PARP-1 defective mice are more sensitive to high levels of high energy irradiation and to alkylating agents, showing that under some condition PARP-1 inactivation can facilitate cell death [35].…”

The pathogenesis of diabetic complications: the role of DNA injury and poly(ADP-ribose) polymerase activation in peroxynitrite-mediated cytotoxicity

“…On the other hand, overactivation of PARP represents an important mechanism of tissue damage in various pathological conditions associated with oxidative and nitrosative stress, including myocardial reperfusion injury (Zingarelli et al 1998), heart transplantation , heart failure (Pacher et al 2002b, c), stroke (Eliasson et al 1997), circulatory shock (Szabó et al 1997a, Oliver et al 1999, Jagtap et al 2002, Shimoda et al 2003, and autoimmune beta-cell destruction associated with diabetes mellitus (Burkart et al 1999, Pieper et al 1999. Activation of PARP and beneficial effects of various PARP inhibitors have been demonstrated in various forms of endothelial dysfunction such as the one associated with circulatory shock, hypertension, atherosclerosis, preeclampsia and aging (Szabó et al 1997, Hung et al 2002, Martinet et al 2002.…”