Noncleavable poly(ADP-ribose) polymerase-1 regulates the inflammation response in mice.
Poly(ADP-ribosyl)ation is rapidly formed in cells following DNA damage and is regulated by poly(ADP-ribose) polymerase-1 (PARP-1). PARP-1 is known to be involved in various cellular processes, such as DNA repair, genomic stability, transcription, and cell death. During apoptosis, PARP-1 is cleaved by caspases to generate 89-kDa and 24-kDa fragments, a hallmark of apoptosis. This cleavage is thought to be a regulatory event for cellular death. In order to understand the biological significance of PARP-1 cleavage, we generated a PARP-1 knockin (PARP-1(KI/KI)) mouse model, in which the caspase cleavage site of PARP-1, DEVD(214), was mutated to render the protein resistant to caspases during apoptosis. While PARP-1(KI/KI) mice developed normally, they were highly resistant to endotoxic shock and to intestinal and renal ischemia-reperfusions, which were associated with reduced inflammatory responses in the target tissues and cells due to the compromised production of specific inflammatory mediators. Despite normal binding of NF-kappaB to DNA, NF-kappaB-mediated transcription activity was impaired in the presence of caspase-resistant PARP-1. This study provides a novel insight into the function of PARP-1 in inflammation and ischemia-related pathophysiologies.
International Agency for Research on Cancer, 69008 Lyons, France.
Virginie
V
Pétrilli
Zdenko
Z
Herceg
Paul O
PO
Hassa
Nimesh S A
NS
Patel
Rosanna
R
Di Paola
Ulrich
U
Cortes
Laura
L
Dugo
Helder-Mota
HM
Filipe
Christoph
C
Thiemermann
Michael O
MO
Hottiger
Salvatore
S
Cuzzocrea
Zhao-Qi
ZQ
Wang
D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D061945:Caspase Inhibitors; D020169:Caspases / Q000378:metabolism*; D002478:Cells, Cultured; D005786:Gene Expression Regulation; D006801:Humans; D007082:Ileum / Q000166:cytology / Q000378:metabolism / Q000473:pathology; D007249:Inflammation / Q000201:enzymology*; D007375:Interleukin-1 / Q000378:metabolism; D007668:Kidney / Q000166:cytology / Q000378:metabolism / Q000473:pathology; D008070:Lipopolysaccharides / Q000276:immunology / Q000494:pharmacology; D008264:Macrophages / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D016328:NF-kappa B / Q000378:metabolism; D019001:Nitric Oxide Synthase / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II; D018384:Oxidative Stress; D017354:Point Mutation; D000071137:Poly (ADP-Ribose) Polymerase-1; D011065:Poly(ADP-ribose) Polymerases / Q000235:genetics / Q000378:metabolism*; D011995:Recombination, Genetic; D015427:Reperfusion Injury / Q000378:metabolism* / Q000473:pathology; D012772:Shock, Septic / Q000378:metabolism; D014158:Transcription, Genetic; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
D061945:Caspase Inhibitors; D007375:Interleukin-1; D008070:Lipopolysaccharides; D016328:NF-kappa B; D014409:Tumor Necrosis Factor-alpha; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; C499321:Parp1 protein, mouse; D000071137:Poly (ADP-Ribose) Polymerase-1; D011065:Poly(ADP-ribose) Polymerases; D020169:Caspases