Role of poly(ADP-ribose) glycohydrolase in the development of inflammatory bowel disease in mice.
Poly(ADP-ribose) is synthesized from nicotinamide adenine dinucleotide (NAD) by poly(ADP-ribose) polymerase 1 (PARP-1) and degraded by poly(ADP-ribose) glycohydrolase (PARG). The aim of the present study was to examine the role of PARG in the development of experimental colitis. To address this question, we used an experimental model of colitis, induced by dinitrobenzene sulfonic acid (DNBS). Mice lacking the functional 110-kDa isoform of PARG (PARG(110)KO mice) were resistant to colon injury induced by DNBS. The mucosa of colon tissues showed reduction of myeloperoxidase activity and attenuated staining for intercellular adhesion molecule 1 and vascular cell adhesion molecule 1. Moreover, overproduction of proinflammatory factors TNF-alpha and IL-1beta and activation of cell death signaling pathway, i.e., the FAS ligand, were inhibited in these mutant mice. Finally pharmacological treatment of WT mice with GPI 16552 and 18214, two novel PARG inhibitors, showed a significant protective effect in DNBS-induced colitis. These genetic and pharmacological studies demonstrate that PARG modulates the inflammatory response and tissue injury events associated with colitis and PARG may be considered as a novel target for pharmacological intervention for the pathogenesis.
Cuzzocrea
Salvatore
S
Department of Clinical and Experimental Medicine and Pharmacology, Torre Biologica, Policlinico Universitario, 98123 Messina, Italy. salvator@unime.it
Mazzon
Emanuela
E
Genovese
Tiziana
T
Crisafulli
Concetta
C
Min
Woo-Kee
WK
Di Paola
Rosanna
R
Muià
Carmelo
C
Li
Jia-He
JH
Malleo
Giuseppe
G
Xu
Weizhen
W
Massuda
Edmond
E
Esposito
Emanuela
E
Zhang
Jie
J
Wang
Zhao-Qi
ZQ
D000818:Animals; D001557:Benzenesulfonates / Q000633:toxicity; D016923:Cell Death; D003092:Colitis / Q000139:chemically induced / Q000201:enzymology / Q000628:therapy*; D004195:Disease Models, Animal; D053222:Fas Ligand Protein / Q000378:metabolism; D006026:Glycoside Hydrolases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000502:physiology*; D015212:Inflammatory Bowel Diseases / Q000139:chemically induced / Q000201:enzymology / Q000628:therapy*; D053583:Interleukin-1beta / Q000378:metabolism; D051379:Mice; D009195:Peroxidase / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
D001557:Benzenesulfonates; D053222:Fas Ligand Protein; D053583:Interleukin-1beta; D014409:Tumor Necrosis Factor-alpha; C007488:dinitrobenzenesulfonic acid; D009195:Peroxidase; D006026:Glycoside Hydrolases; C022407:poly ADP-ribose glycohydrolase