Antisense oligonucleotides to poly(ADP-ribose) polymerase-2 ameliorate colitis in interleukin-10-deficient mice.
poly(ADP-ribose) polymerase-2 (PARP-2) is a newly described member of the PARP family of nuclear enzymes. Previous studies have shown pharmacological inhibition of PARP activity to have a beneficial role in attenuating inflammation. We developed a chemically modified 2'-O-(2-methoxy)ethyl antisense oligonucleotide (ISIS 110251) inhibitor of PARP-2 and tested it for efficacy in the interleukin (IL)-10-deficient mouse. In tissue culture, ISIS 110251 reduced PARP-2 mRNA expression in a concentration- and sequence-specific manner. In 129 Sv/Ev mice, ISIS 110251 reduced PARP-2 mRNA in liver by 80%. This reduction was dependent upon treatment duration and was independent of the method of delivery. In interleukin-10-deficient mice with established colitis, treatment with ISIS 110251 normalized colonic epithelial barrier and transport function, reduced proinflammatory cytokine secretion and inducible nitric-oxide synthase activity, and attenuated inflammation. Our data demonstrate that selective inhibition of PARP-2 activity results in a marked improvement of colonic inflammatory disease in a mouse model of chronic colitis and a normalization of colonic function.
Popoff
Ian
I
Division of Gastroenterology, University of Alberta, Edmonton, Alberta, Canada.
Jijon
Humberto
H
Monia
Brett
B
Tavernini
Michele
M
Ma
Michael
M
McKay
Rob
R
Madsen
Karen
K
D000818:Animals; D003092:Colitis / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics / Q000473:pathology; D003106:Colon / Q000187:drug effects / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D016753:Interleukin-10 / Q000172:deficiency* / Q000235:genetics*; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D016376:Oligonucleotides, Antisense / Q000235:genetics / Q000494:pharmacology / Q000627:therapeutic use*; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D011065:Poly(ADP-ribose) Polymerases / Q000096:biosynthesis; D012333:RNA, Messenger / Q000037:antagonists & inhibitors / Q000096:biosynthesis
D016376:Oligonucleotides, Antisense; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D012333:RNA, Messenger; D016753:Interleukin-10; D011065:Poly(ADP-ribose) Polymerases; C459820:Parp2 protein, mouse